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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 Kidney Diseases :... Jul 2015Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with advanced chronic kidney disease and end-stage renal disease. No study has specifically compared the risks of hard study outcomes between EPO and DPO, including mortality.
STUDY DESIGN
Systematic review of the literature and meta-analysis.
SETTING & POPULATION
Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis.
SELECTION CRITERIA FOR STUDIES
We conducted a systematic search of the literature (PubMed, CENTRAL, SCOPUS, and EMBASE, all years) and industry resources, using predefined search terms and data abstraction tools. We then summarized key characteristics and findings of these trials and performed a random-effects meta-analysis of trials with at least 3 months' duration to identify the summary OR of mortality between patients randomly assigned to DPO versus EPO.
INTERVENTION
DPO versus EPO.
OUTCOME
All-cause mortality.
RESULTS
We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic=4.60; P=0.8).
LIMITATIONS
Generalizability to nontrial populations is uncertain.
CONCLUSIONS
Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO. Absent adequately powered randomized trials, observational postmarketing comparative effectiveness studies comparing these erythropoiesis-stimulating agents are required to better characterize the long-term safety profiles of these agents.
Topics: Anemia; Cause of Death; Darbepoetin alfa; Double-Blind Method; Epoetin Alfa; Erythropoietin; Half-Life; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 25636816
DOI: 10.1053/j.ajkd.2014.12.012 -
Current Medical Research and Opinion Dec 2006The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in... (Review)
Review
OBJECTIVE
The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in chronic kidney disease (CKD) and to identify determinants of the variation in epoetin alfa:darbepoetin alfa dose ratios across studies.
METHODS
A systematic review of the literature for comparative switch and non-switch studies of epoetin alfa and darbepoetin alfa treatments in CKD for the period 2000-2005 was performed. Two reviewers independently assessed the quality of the information. Data on the study design and outcomes were collected for each selected study. The dose ratio from epoetin alfa to darbepoetin alfa was calculated for each study, and the results were reported stratified by study characteristics. To control for differences in study design and characteristics that could explain the variability in the relative dosages of the two agents across studies, multivariate regression analysis was conducted. Based on these results, a dose conversion ratio for Canada was estimated.
RESULTS
A total of 21 studies involving 16 378 patients exposed to epoetin alfa or darbepoetin alfa in CKD were identified. Univariate analysis of the dose ratios indicated a mean dose ratio of 217:1 (IU of epoetin alfa:mug of darbepoetin alfa). Results from the multivariate analysis demonstrated that the study design (i.e., switch study versus straight comparison studies) and geographical coverage (i.e., United States) affected the results. Based on the multivariate analysis, the dose conversion ratio between epoetin alfa and darbepoetin alfa for Canada was 169:1.
CONCLUSIONS
Despite limitations associated with switching studies and the limited total number of studies available, this systematic review based on aggregated results provides further evidence to the clinical community that the dose conversion ratio for epoetin alfa:darbepoetin alfa in CKD patients in Canada is approximately 169:1. At that ratio, treatment with epoetin alfa is 11-18% cheaper than treatment with darbepoetin alfa in Canada.
Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Multivariate Analysis; Recombinant Proteins
PubMed: 17257447
DOI: 10.1185/030079906X154024 -
International Journal of Clinical... Dec 2014Anemia management in non-dialysis-dependent chronic kidney disease (CKD) patients is associated with cardiovascular and cost benefits, slows decline in renal function,... (Comparative Study)
Comparative Study Review
BACKGROUND
Anemia management in non-dialysis-dependent chronic kidney disease (CKD) patients is associated with cardiovascular and cost benefits, slows decline in renal function, and prevents mortality. Different reviews have focused on evaluating the safety and efficacy of methoxy polyethylene glycol-epoetin beta (MPG-EPO), a continuous erythropoietin receptor activator, in CKD patients regardless of dialysis dependency and others have studied this novel agent exclusively in CKD patients receiving dialysis.
AIM OF THE REVIEW
To evaluate the efficacy and tolerability of MPG-EPO compared with other erythropoiesis stimulating agents (in particular darbepoetin alfa) for the treatment of anemia in non-dialysis-dependent CKD patients.
METHODS
A systematic review of original studies published mainly in MEDLINE, Cochrane Database, ScienceDirect, ProQuest, clinical trials registries, and Google Scholar was carried out to identify randomized controlled trials (RCTs) comparing MPG-EPO with other erythropoiesis stimulating agents or placebo among patients with anemia of CKD who were not yet receiving dialysis. Data were independently extracted by two reviewers using standardized data abstraction tool.
RESULTS
Four trials involving 1,155 patients were included in the review. The changes in hemoglobin level from the baseline reported by the reviewed studies demonstrate that MPG-EPO was clinically non-inferior to darbepoetin alfa. In addition, the studies documented that MPG-EPO-treated patients experienced a lower rate of hemoglobin level above the target range of 12-13 g/dL than darbepoetin-treated patients. The proportion of patients requiring RBC transfusion was higher among patients who received darbepoetin alfa than those who received MPG-EPO. However, the time to hemoglobin response was longer with MPG-EPO than with darbepoetin. Finally, the incidences of serious adverse events were similar between the two therapeutic agents.
CONCLUSION
There are currently only few well-designed head-to-head RCTs investigating the efficacy and safety of MPG-EPO compared with other ESAs in non-dialysis-dependent patients. MPG-EPO therapy compared with darbepoetin alfa has demonstrated favorable effects of increasing and maintaining hemoglobin concentrations to recommended target levels. This mini-review is not conclusive due to limited number of studies. Therefore, the beneficial effects and tolerability of MPG-EPO among non-dialysis-dependent CKD patients should be further investigated, given the economic and clinical benefits of managing anemia in this population.
Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 25288147
DOI: 10.1007/s11096-014-0023-x -
Clinical Therapeutics Jun 2006Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the management of CIA do not yet include all currently approved ESPs or all of the clinically relevant benefits and risks of ESPs.
OBJECTIVES
The aims of this work were to provide up-to-date assessments of the clinical efficacy and effectiveness (ie, transfusions and quality-of-life [QoL] benefits) and safety (ie, risk of venous thromboembolism [VTE] and all-cause or treatment-associated death) of epoetin-alfa, epoetin-beta, and darbepoetin-alfa for the treatment of CIA in cancer patients with hemoglobin<11 g/dL. We also considered the impact of differences in study design, patients, and treatments on the results.
METHODS
A systematic review of the literature was performed to identify and analyze English-language studies (controlled trials and prospective uncontrolled studies with >or=300 patients) published between 1980 and July 2005. The databases searched were MEDLINE and the Cochrane Library. Relevant abstracts from the last 2 annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology were also included. Studies were selected, using predefined eligibility criteria. Two reviewers had to agree on all included and excluded studies, and on all data extracted from each accepted study before they were entered into a relational database. Meta-analyses were performed to quantify benefit and risk outcomes.
RESULTS
In total, 40 studies including 21,378 patients were eligible for analysis. Each ESP was found to have efficacy relative to standard care or placebo. The odds ratio (OR) for transfusions in studies of epoetin versus controls was 0.44 (95% CI, 0.35-0.55) and of darbepoetin versus controls was 0.41 (95% CI, 0.31-0.55). Patients receiving ESPs experienced a significant improvement in QoL; the mean difference in Functional Assessment of Cancer Therapy-Fatigue score for ESPs versus controls was 0.23 (95% CI, 0.10-0.36; P=0.001). The frequency of VTE and death was not significantly different between ESPs and control (VTE OR, 1.41 [95% CI, 0.81-2.47]; all-cause mortality OR, 1.00 [95% CI, 0.69-1.44]).
CONCLUSIONS
This analysis of key clinical benefits and risks of epoetin and darbepoetin in the treatment of CIA found no clinically relevant differences between these drugs.
Topics: Adult; Anemia; Antineoplastic Agents; Blood Transfusion; Child; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Quality of Life; Recombinant Proteins; Thromboembolism; Venous Thrombosis
PubMed: 16860166
DOI: 10.1016/j.clinthera.2006.06.003 -
British Journal of Haematology Sep 2016We conducted a systematic review and meta-analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)-related anaemia.... (Meta-Analysis)
Meta-Analysis Review
We conducted a systematic review and meta-analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)-related anaemia. Eligible studies were prospective, interventional, and reported World Health Organization, French-American-British, or International Prognostic Scoring System (IPSS) criteria. Outcomes included erythroid response rate (primary); haemoglobin response; change in haemoglobin, transfusion status, and quality-of-life (QoL); and safety. Ten studies (N = 647) were analysed. Erythroid response rate range was 38-72%; median response duration range was 12-51+ months. Patients with erythropoietin (EPO) <100 iu/l had 35% [95% confidence interval (CI): 22-48%; P < 0·001) better response than patients with EPO >100 iu/l. Erythropoesis-stimulating agent (ESA)-naïve patients had 17% (95% CI: 3-32%; P = 0·022) greater response rate than those previously treated with ESA. Nonetheless, previously treated patients had response rates of 25-75%. Higher baseline haemoglobin levels, higher dose, transfusion-independence and low-risk IPSS status were reported by several studies to be associated with better response. QoL, transfusion rates and haemoglobin levels improved with treatment. Hypertension, thromboembolism and progression to acute myeloid leukaemia were reported in 2%, 1% and 1% of patients, respectively. This meta-analysis suggests that DA treatment can be useful for improving erythroid response in MDS patients with anaemia, even among patients previously treated with ESA.
Topics: Blood Transfusion; Darbepoetin alfa; Hemoglobins; Humans; Myelodysplastic Syndromes; Quality of Life; Treatment Outcome
PubMed: 27214305
DOI: 10.1111/bjh.14116 -
Health Technology Assessment... Apr 2007To assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia... (Review)
Review
A systematic review and economic evaluation of epoetin alpha, epoetin beta and darbepoetin alpha in anaemia associated with cancer, especially that attributable to cancer treatment.
OBJECTIVES
To assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment.
DATA SOURCES
Electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004.
REVIEW METHODS
Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model).
RESULTS
In total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound 10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound 13,000 to pound 28,000, but generated estimates from pound 84,000 to pound 159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound 150,000, falling to pound 40,000 when the lower, more favourable, confidence interval for survival was used.
CONCLUSIONS
Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.
Topics: Anemia; Antineoplastic Agents; Cost-Benefit Analysis; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis; Treatment Outcome
PubMed: 17408534
DOI: 10.3310/hta11130 -
Annals of Hematology Jul 2008The present meta-analysis was undertaken to (1) assess erythroid response rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa as a monotherapy,... (Comparative Study)
Comparative Study Meta-Analysis Review
The present meta-analysis was undertaken to (1) assess erythroid response rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa as a monotherapy, (2) gain further insights into predictors of response rates, and (3) compare the erythroid response rates observed with epoetin alfa and darbepoetin alfa. A systematic review of studies from 1990 to 2006 in MDS patients treated with epoetin alfa or darbepoetin alfa was performed and yielded 30 studies evaluating a total of 1,314 patients (epoetin alfa: 22 studies, 925 patients; darbepoetin alfa: eight studies, 389 patients). Pooled estimates of erythroid response rates, stratified by the International Working Group criteria (IWGc) and treatment group, were calculated using random-effects meta-analysis methods. Univariate meta-regression analyses were further conducted to identify study characteristics associated with erythroid response rate. The pooled estimate of erythroid response rate was significantly higher for epoetin alfa IWGc studies (57.6%) as compared to non-IWGc studies (31.6%; p < 0.001). Study factors predictive of higher response rate in the epoetin alfa IWGc studies included higher proportion of patients with RA/RARS (p < 0.001), lower mean baseline serum erythropoietin level (p = 0.007), and fixed dosing regimen (p < 0.001). There was no significant difference in the pooled erythroid response rates between the two agents (epoetin alfa: 57.6% vs. darbepoetin alfa: 59.4%; p = 0.828). The current study reported significantly higher erythroid response rates predominantly in the more recent studies that primarily utilized IWGc to define response. With the use of standardized patient selection and response evaluation methods, epoetin alfa and darbepoetin alfa yielded comparable erythroid response rates in MDS patients.
Topics: Aged; Anemia; Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Evaluation; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome
PubMed: 18351340
DOI: 10.1007/s00277-008-0450-7 -
Frontiers in Pharmacology 2021Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the... (Review)
Review
Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia. PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach. Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included ( = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: -54.95 to -18.30; < 0.001) and ferritin (MD -56.24; 95% CI: -77.37 to -35.11; < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke. Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.
PubMed: 35115942
DOI: 10.3389/fphar.2021.795214 -
PharmacoEconomics 2008Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that are used in the treatment of anaemia. Their successful use in the... (Review)
Review
Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that are used in the treatment of anaemia. Their successful use in the treatment of anaemia associated with renal disease, cancer and other diseases, as well as the development of multiple agents, has increased the visibility of these agents in the clinical and health economics literature. The circumstances under which the use of ESAs is cost effective, or indeed, whether it is cost effective, is of central concern for clinicians and payers who must make informed decisions regarding the management of these costly resources. Much of the recent literature on ESAs in the treatment of anaemia associated with chronic kidney disease and cancer, the two major therapeutic areas for ESA treatment, has focused on comparisons between individual ESAs, particularly epoetin alfa and darbepoetin alfa. While there have been some studies of cost effectiveness, many studies in these treatment areas have employed a cost-minimization approach and have relied on published prices rather than actual market prices. In general, this review of the literature suggests a cost advantage for epoetin alfa relative to darbepoetin alfa in the treatment of anaemia in renal and oncology indications. For other indications in which the literature is less developed, such as anaemia induced by antiviral therapy and blood management in surgery, small prospective studies or decision-analytic models comparing ESA therapy and standard care have been most common. Few conclusions can be drawn about the overall and relative costs or cost effectiveness of ESAs in these treatment areas. With the recent concerns about the safety of ESAs, especially when used outside the approved product labelling, future evaluations of epoetin alfa and darbepoetin alfa should factor their safety profiles into estimates of cost effectiveness. Moreover, additional studies are needed to evaluate whether the treatment of anaemia with ESAs is cost effective compared with no treatment or minimal blood transfusions, and whether the cost effectiveness of ESAs would be improved if ESA doses and durations were reduced. With the introduction of new longer-acting ESAs, such as the continuous erythropoietin receptor activator, the relative cost effectiveness among the different ESAs will continue to be an important question for public and private payers, policy makers and clinicians who must consider the emergence of new data and changing dosing patterns when making decisions about the use of these important but costly agents.
Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins
PubMed: 18198931
DOI: 10.2165/00019053-200826020-00002