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The New England Journal of Medicine Apr 2021Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.
METHODS
We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).
RESULTS
A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.
CONCLUSIONS
Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNOVATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
Topics: Aged; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Picolinic Acids; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 33913638
DOI: 10.1056/NEJMoa2025956 -
The Lancet. Haematology Dec 2023
Topics: Humans; Infant, Newborn; Anemia; Darbepoetin alfa; Erythropoietin; Fetus; Hematologic Diseases; Hemolysis
PubMed: 38030313
DOI: 10.1016/S2352-3026(23)00316-2 -
The New England Journal of Medicine Apr 2021Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.
METHODS
In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.
RESULTS
A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.
CONCLUSIONS
Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PROTECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
Topics: Administration, Oral; Aged; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Female; Glycine; Hematinics; Hemoglobins; Hospitalization; Humans; Male; Middle Aged; Picolinic Acids; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic
PubMed: 33913637
DOI: 10.1056/NEJMoa2035938 -
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 -
American Journal of Health-system... Oct 2023Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin...
PURPOSE
Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial.
METHODS
This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 μg and those who received a weight-based dose of 0.45 μg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation.
RESULTS
Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 μg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups.
CONCLUSION
Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.
Topics: Humans; Darbepoetin alfa; Kidney Transplantation; Retrospective Studies; Anemia; Hemoglobins; Hematinics; Treatment Outcome
PubMed: 37471466
DOI: 10.1093/ajhp/zxad163 -
American Journal of Kidney Diseases :... Oct 2002
Topics: Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Therapeutic Equivalency
PubMed: 12324929
DOI: 10.1053/ajkd.2002.36566 -
Expert Opinion on Pharmacotherapy Mar 2005Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy.... (Review)
Review
Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.
Topics: Anemia; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Hemoglobins; Humans; Neoplasms; Recombinant Proteins
PubMed: 15794734
DOI: 10.1517/14656566.6.3.429 -
International Urology and Nephrology Oct 2020Anemia is a common complication in dialysis patients, usually treated with erythropoietin (EPO). Among available EPOs and analogs, continuous erythropoietin receptor...
PURPOSE
Anemia is a common complication in dialysis patients, usually treated with erythropoietin (EPO). Among available EPOs and analogs, continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) are the only two agents with a long duration of action, although they have almost never been formally compared in terms of efficacy. We took advantage of an accidental disruption in CERA supply to study the effect of its replacement with DA in the same patients.
METHODS
The clinical and biological characteristics of 154 hemodialysis patients were retrospectively reviewed during the last 3 months on CERA compared to the first 4 months after replacement by DA, both ASE being administered by IV route. The comparison included EPO doses, hemoglobin levels, factors interfering with anemia (iron status assessment, iron doses, inflammation, quality of treatment) and was performed under the Bayesian paradigm.
RESULTS
We found no significant differences between the two EPOs in terms of doses or hemoglobin concentrations. Factors that could potentially influence hemoglobin concentrations also did not differ under CERA or DA. The stability of hemoglobin was identical with both EPOs. We provide a conversion factor which allows comparison of cost according to local prices.
CONCLUSIONS
We conclude that, in this observational "real life" study, the two EPOs are to be considered as equivalent.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Substitution; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Retrospective Studies; Young Adult
PubMed: 32725508
DOI: 10.1007/s11255-020-02569-w -
British Journal of Cancer Jul 2002In part A of this study, patients were randomised to cohorts receiving darbepoetin alfa at doses of 0.5 to 8.0 m.c.g x kg(-1) x wk(-1) or to a control group receiving... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
In part A of this study, patients were randomised to cohorts receiving darbepoetin alfa at doses of 0.5 to 8.0 m.c.g x kg(-1) x wk(-1) or to a control group receiving epoetin alfa at an initial dose of 150 U x kg(-1) three times weekly. In part B, the cohorts were darbepoetin alfa 3.0 to 9.0 m.c.g x kg(-1) every 2 weeks or epoetin alfa, initial dose 40 000 U x wk(-1). Safety was assessed by adverse events, changes in blood pressure, and formation of antibodies to darbepoetin alfa. Efficacy was assessed by several haematologic endpoints, including change in haemoglobin from baseline. The adverse event profile of darbepoetin alfa was similar to that of epoetin alfa. No relationship between the rapidity of haemoglobin response and any adverse event was observed. No antibodies to darbepoetin alfa were detected. Higher doses of darbepoetin alfa increased the proportion of patients with a haemoglobin response and decreased the median time to response. The overall dose of darbepoetin alfa required to produce a mean increase in haemoglobin does not increase when the dosing interval is increased from 1 to 2 weeks. Therapy with darbepoetin alfa is safe and effective in producing a dose-related increase in haemoglobin levels in patients with cancer receiving chemotherapy.
Topics: Adult; Aged; Anemia; Antineoplastic Agents; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Recombinant Proteins
PubMed: 12177793
DOI: 10.1038/sj.bjc.6600465 -
American Journal of Nephrology 2022Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production.
METHODS
To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm.
RESULTS
In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events.
DISCUSSION/CONCLUSION
Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
Topics: Humans; Darbepoetin alfa; Quality of Life; Anemia; Erythropoietin; Renal Insufficiency, Chronic; Hematinics; Renal Dialysis; Hemoglobins
PubMed: 36450264
DOI: 10.1159/000528443