Erythropoiesis-stimulating Agents Group Research Articles

Erythrocyte indices and response to hypoxia-inducible factor prolyl hydroxylase inhibitors in chronic kidney disease patients with renal anemia: a retrospective study

BackgroundAlthough erythropoiesis-stimulating agents (ESAs) have been the standard treatment for renal anemia, ESA hyporesponsiveness remains a concern. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of agents indicated for renal anemia. Several lines of evidence indicate that HIF-PHIs affect erythrocyte indices; nonetheless, their clinical significance remains unclear.MethodsWe retrospectively analyzed data from 233 non-dialysis-dependent chronic kidney disease patients who initiated either ESA (darbepoetin) or HIF-PHI for the treatment of anemia. We analyzed the changes in hemoglobin levels three months after the initiation of anti-anemic treatments, examining their association with changes in erythrocyte indices.ResultsBoth ESA and HIF-PHIs significantly increased hemoglobin levels after three months of treatment. In the HIF-PHI group, the increase in hemoglobin levels was positively correlated with the increase in mean corpuscular volume (MCV) levels, a finding that was not observed in the ESA group. In a subgroup analysis based on the mean reference range value for MCV (90.9 fL), a significant difference in the proportion of patients with improved anemia was observed between ESA and HIF-PHIs in patients with lower MCV values. Logistic regression and interaction analyses confirmed that there was a significant interaction between baseline MCV values and the effectiveness of anti-anemic drugs, independently of other covariates.ConclusionsAn increase in hemoglobin levels is associated with an increase in MCV in patients treated with HIF-PHIs. The anti-anemic effects of ESA and HIF-PHIs may be influenced by baseline MCV values. However, long-term consequences need further evaluation.

Iron Deficiency in Newly Referred Patients With Chronic Renal Failure.

Addressing iron deficiency is the key to managing anemia in patients with chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) are being prescribed to an increasing number of patients with CKD by primary physicians following the emergence of newer agents for the management of renal anemia. Among the 361 (average age: 76.8±12.1 years; 54.0% males) patients with stages 4 and 5 CKD newly referred to the nephrology department of our hospital between 2018 and 2023 who had evaluable transferrin saturation (TSAT) and ferritin levels, 169 patients (47%) had iron deficiency (ferritin <100 ng/mL or ferritin 100-300 ng/mL with TSAT <20%). The estimated glomerular filtration rate (eGFR), hemoglobin level, TSAT, and median ferritin level were 17.0±7.0 mL/min/1.73 m², 10.8±2.1 g/dL, 27.5±13.1%, and 130 ng/mL, respectively. ESAs, HIF-PHIs, and iron supplements were prescribed to 35 (9.7%), 17 (4.7%), and 35 (9.4%) patients, respectively. No significant differences were observed between the iron indices of the ESA group; however, the serum ferritin levels in the HIF-PHIs group were significantly lower than in those in the no-medication group (P=0.02). Multivariable logistic regression analysis revealed that age, female sex, eGFR, medications for renal anemia, and a history of ischemic heart disease were associated with iron deficiency (P<0.05). Although patients with renal failure tend to exhibit anemia, attention should be paid to iron deficiency anemia in addition to renal anemia, especially in patients with renal failure and a history of ischemic heart disease.

The efficacy and safety of molidustat for anemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis

ObjectiveMolidustat is a novel agent investigated for the treatment of anemia in both dialysisdependent (DD) and non-dialysis-dependent (NDD) patients. Its efficacy and safety are still unclear. MethodsWe searched five databases to identify randomized controlled trials comparing molidustat to erythropoiesis-stimulating agents (ESAs) or placebo in patients with anemia. ResultsSix studies containing 2025 eligible participants were identified. For NDD patients, the change in Hb levels from baseline (ΔHb) was significantly higher for molidustat than for placebo [mean difference (MD) = 1.47 (95 % CI: 1.18 to 1.75), P < 0.00001] and ΔHb was also significantly higher for molidustat than for ESAs [MD = 0.25 (95 % CI 0.09 to 0.40), P = 0.002]. For NDD patients, Δhepcidin was significantly lower for molidustat than for placebo [MD = −20.66 (95 % CI: −31.67 to −9.66), P = 0.0002] and Δhepcidin was also significantly lower for molidustat than for ESAs [MD = −24.51 (95 % CI: −29.12 to −19.90), P < 0.00001]. For NDD patients, Δiron was significantly lower for molidustat than for ESAs [MD = −11.85 (95 % CI: −15.52 to −8.18), P < 0.00001], and ΔTSAT was also significantly lower for molidustat than for ESAs [MD = −5.29 (95 % CI: −6.81 to −3.78), P < 0.00001]. For NDD patients, Δferritin was significantly lower for molidustat than for placebo [MD = −90.01 (95 % CI: −134.77 to −45.25), P < 0.00001]. However, for DD-CKD patients, molidustat showed an effect similar to that of ESAs on increasing the Hb level [MD = −0.18 (95 % CI: −0.47 to 0.11), P = 0.23], Δiron level [MD = 3.78 (95 % CI: −7.21 to 14.76), P = 0.5], Δferritin level [MD = 25.03 (95 % CI: −34.69 to 84.75), P = 0.41], and Δhepcidin level [MD = 1.20 (95 % CI: −4.36 to 6.76), P = 0.67]. For DD-CKD patients, compared with the placebo or ESA group, molidustat showed a significantly higher level on ΔTSAT[MD = 3.88 (95 % CI: 2.10 to 5.65), P < 0.0001] and a slightly increased level on ΔTIBC level [MD = 1.08 (95 % CI: −0.07 to 2.23), P = 0.07]. There was no significant difference in the incidence of severe adverse events (SAEs), death, and cardio-related adverse events between molidustat and the ESAs groups. ConclusionsMoricizine can effectively improves Hb levels in NDD patients and corrects anemia in DD patients without increasing adverse event incidence.

Prognostic impact of erythropoietin-stimulating agent use during front-line chemotherapy in patients with ovarian cancer: A Korean multicenter cohort study.

To evaluate whether treatment with erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia affects progression-free survival (PFS) in patients receiving front-line chemotherapy following surgery for ovarian cancer (OC). We retrospectively reviewed all consecutive patients who received front-line chemotherapy after surgery between 2013 and 2019 at six institutions. The patients were divided according to the use of ESAs during front-line chemotherapy. The primary endpoint was PFS. The secondary endpoint was the occurrence of thromboembolism. Propensity score matching (PSM) analysis was used to compare survival between matched cohorts. Overall, 2147 patients (433 receiving ESA and 1714 for no-ESA) were identified, with a median follow-up of 44.0 months. The ESA group showed a significantly higher proportion of stage III/IV disease (81.8% vs 61.1%; P < 0.001) and postoperative gross residual disease (32.3% vs 21.2%; P < 0.001) than the no-ESA group. In the multivariable Cox regression analysis, the use of ESAs did not affect PFS (adjusted hazard ratio, 1.03; 95% confidence interval [CI]: 0.89-1.20; P = 0.661). The incidence of thromboembolism was 10.2% in the ESA group and 4.6% in the no-ESA group (adjusted odds ratio, 6.58; 95% CI: 3.26-13.28; P < 0.001). When comparing the well-matched cohorts after PSM, PFS did not differ between the ESA (median PFS 23.5 months) and no-ESA groups (median PFS 22.2 months) (P = 0.540, log-rank test). The use of ESAs during front-line chemotherapy did not negatively affect PFS in patients with OC after surgery but increased the risk of thromboembolism.

A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.

Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Roxadustat for Treating Anemia in Patients with Advanced Chronic Kidney Disease Not Undergoing Dialysis: A Retrospective Study.

Objective Roxadustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, increases the hemoglobin (Hb) levels in patients with chronic kidney disease (CKD). To date, limited clinical studies have focused on the excessive increase in the Hb levels in the early weeks after switching from erythropoiesis-stimulating agents (ESA) to roxadustat in adult non-dialysis patients. We conducted a retrospective study to examine whether early overshoot frequently occurs after switching to roxadustat. Methods This 8-week retrospective pilot study examined patients with anemic, non-dialyzed CKD who switched from ESA (darbepoetin or epoetin beta pegol) to roxadustat or continued ESA. The Hb levels >12.5 g/dL after starting our observation was defined as Hb overshoot. Patients: Twenty-three patients who switched to roxadustat (roxadustat group) and 63 who continued ESA (ESA group) were included. Results The baseline median estimated glomerular filtration rate and mean Hb levels were 15.7 mL/min/1.73 mShizuokax and 10.77 g/dL in roxadustat group and 15.2 mL/min/1.73 m2 and 10.64 g/dL in ESA group, respectively. Eight patients (34.8%) in the roxadustat group and two patients (3.2%) in the ESA group had Hb overshoot within the 8-week visit (odds ratio: 20.2 [95% confidence interval 3.13-130.0, p<0.01] in the background adjusted model). Among the patients with Hb overshoot in the roxadustat group, the Hb levels were maintained close to baseline 4 weeks after roxadustat discontinuation. A younger age and higher baseline Hb and Hct levels were risk factors for Hb overshoot. Conclusions Hb overshoot was frequently observed in patients switched to roxadustat. Clinicians should be aware of Hb overshoot and emphasize the importance of early Hb level checks.

Hypoxia‐inducible factor prolyl hydroxylase domain inhibitors may mitigate loss of skeletal muscle mass in haemodialysis patients

AbstractBackgroundChronic kidney disease patients particularly with renal anaemia hyporesponsive to erythropoiesis‐stimulating agents (ESAs) are at a greater risk of having skeletal muscle mass (SMM) loss. Hypoxia‐inducible factor prolyl hydroxylase domain inhibitor (HIF‐PHI), a novel therapeutic agent for renal anaemia, potentially promotes angiogenesis, muscle repair, and homeostasis. However, effects of HIF‐PHIs on SMM remain unknown.MethodsThis retrospective observational cohort study enrolled 292 Japanese adults receiving maintenance haemodialysis at our dialysis centre. The dataset included 11 patients who received daprodustat for 6 months or longer during 1 December 2020 through 30 June 2022. From the previously published pooled cohort, we enrolled 281 participants from 1 August 2018 to 31 July 2019 prior to the approval of HIF‐PHIs for renal anaemia. SMM was assessed using modified creatinine index (mg/kg/day) calculated by age, sex, serum creatinine, and single‐pool Kt/V. Annual changes of SMM [ΔSMM (%)] were analysed with the least squares regression model and mixed‐effects model during 6‐ to 12‐month follow‐up period.ResultsThe median age of the participants was 63 years [interquartile range (IQR), 54–71 years], and 33% were female. The median ΔSMM levels (IQR) in the least squares regression model were 4.0% (−1.7% to 9.3%) in the HIF‐PHI group, 0.20% (−2.1% to 2.1%) in the no ESA group, and −0.94% (−3.0% to 1.3%) in the high ESA group using darbepoetin equivalent to 20 μg or more per week. Those in the mixed‐effects model were −1.7% (−1.2% to 3.8%), 0.09% (−1.4% to 1.3%), and −0.74% (−2.0% to 0.8%), respectively. The multivariable linear regression models revealed that HIF‐PHI use was associated with greater ΔSMM compared with the high ESA group [coefficient, 3.737; 95% confidence interval (CI), 1.216–6.258 in the least squares regression model or coefficient, 1.635; 95% CI, 0.068–3.201 in the mixed‐effects model, respectively].ConclusionsHIF‐PHI use led to greater ΔSMM in maintenance haemodialysis patients. HIF‐PHIs may minimize loss of SMM in patients with end‐stage kidney disease and renal anaemia.

Effect of roxadustat on iron metabolism in patients with peritoneal dialysis: a real-world 24-week study

BackgroundRoxadustat is an oral hypoxia inducing factor-prolyl hydroxylase inhibitor (HIF-PHI) that regulates iron metabolism in patients with chronic kidney disease (CKD) primarily by reducing hepcidin levels and mobilizing internal iron stores. More data are needed to demonstrate the efficacy of roxadustat in regulating iron metabolism in patients with peritoneal dialysis (PD) compared with erythropoiesis stimulating agents (ESAs).MethodsThis prospective cohort study enrolled PD patients with a mean hemoglobin level of 60–100 g/L. All subjects were randomized into two groups at a ratio of 2:1 the roxadustat group (106 cases), and the ESA group (53 cases). The primary endpoint was the change in the iron biomarker levels and the proportion of patients with absolute iron deficiency and functional iron deficiency.ResultsCompared with ESAs, roxadustat significantly decreased hepcidin level (difference, − 20.09 ng/mL; 95% CI, − 30.26 to − 9.92), attenuated the increase in serum soluble transferrin receptor (sTFR) level (difference, − 7.87 nmol/L; 95% CI, − 12.11 to − 3.64), and reduced the proportion of patients with functional iron deficiency (roxadustat, 11.43%; ESA, 33.33%). There was no significant difference in safety of the two groups over the duration of the study.ConclusionsCompared with ESA group, roxadustat group showed significant differences in all iron biomarker levels except serum ferritin (sFt) and transferrin saturation (TSAT). These results suggest that roxadustat was superior to ESAs as a therapy for iron metabolism in PD patients.Trial registration: This study completed Chinese Clinical Trial Registration on March 4, 2022 (registration number: ChiCTR2200057231).Graphical abstract

Longitudinal Assessment of Preterm Infants Treated with Erythropoiesis Stimulating Agents.

We previously reported improved neurodevelopment at 2 and 4 years among preterm infants treated with erythropoietin or darbepoetin, known as erythropoiesis-stimulating agents (ESAs). We now characterize longitudinal outcomes through 6 years. Children randomized to ESAs or placebo were evaluated at 6 years. Healthy-term children served as controls. Tests of cognition and executive function (EF) were performed. Cognitive/EF scores remained similar between 4 and 6 years within each group (ESA: 43 children; placebo: 17 children; term: 21 children). ESA recipients scored higher than placebo on Full-Scale IQ (94.2±18.6 vs 81.6±16.7, p=0.022), and Performance IQ (97.3±16.2 vs 81.7±15.2, =0.005). Aggregate EF trended better for the ESA group. Term controls scored better than placebo on all measures. ESA and term controls scored similarly on cognitive and EF tests. ESA recipients had better outcomes than placebo recipients, and were similar to term children. ESAs may improve long-term cognition and executive function in preterm infants.

Association of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors with Cardiovascular Events and Death in Dialysis Patients: A Systematic Review and Meta-Analysis

Background: Anemia is a common finding among patients with advanced chronic kidney disease, especially those on dialysis. The recent introduction of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) has raised some concerns about the cardiovascular and thrombotic complications of this class of drugs. Objectives: This meta-analysis aimed to assess the safety of HIF-PHIs in patients with end-stage kidney disease (ESKD) versus standard therapy with erythropoiesis-stimulating agents (ESAs). Methods: Databases were searched on April 2022. Studies that reported incidence of all-cause mortality; major cardiovascular adverse events (MACEs); myocardial infarction (MI); stroke and thrombotic events in the use of HIF-PHIs or ESA on ESKD patients in hemodialysis or peritoneal dialysis were evaluated. Data were extracted from published reports, and quality assessment was performed per Cochrane recommendations. Results: 12,821 patients from ten randomized controlled trials were included in this study. Most patients (83%) were on hemodialysis. 6,461 (50.3%) were using HIF-PHIs, and 6,360 (49.6%) were in the ESA group. The pooled estimated incidence of all-cause mortality was 769 in the HIF-PHIs group (relative-risk ratios (RR): 1.04; confidence interval (CI): 0.95–1.14; p = 0.52; I² = 0%). There was no difference in the groups regarding the outcomes of MACE in the analysis of the three studies that reported this outcome (RR: 0.95; CI: 0.87–1.04; p = 0.69; I² = 0%). In addition, there was no statistical difference among the outcomes of MI, stroke, or thrombotic events. Conclusions: Among patients with ESKD on dialysis, the use of HIF-PHIs was non-inferior regarding the safety outcomes when compared to standard of care therapy.

#3715 THE EFFECT OF DAPRODUSTAT ON INTRAVENOUS IRON USE IN PATIENTS WITH CKD-RELATED ANAEMIA ON DIALYSIS IN THE ASCEND TRIALS

Abstract Background and Aims Intravenous (IV) iron is frequently needed in patients with chronic kidney disease (CKD) to ensure sufficient iron is available for erythropoiesis. However high doses of IV iron and erythropoiesis stimulating agents (ESAs) may be associated with risks in these patients [1]. The hypoxia-inducible factor-prolyl hydroxylase domain inhibitor daprodustat was non-inferior to comparator ESAs for the primary endpoint of efficacy (change-in-Hb) in the multicentre, randomised, Phase 3 trials ASCEND-D (NCT02879305) [2] and ASCEND-TD (NCT03400033) [3], also for the safety (major adverse cardiovascular [CV] events) coprimary endpoint in ASCEND-D [2]. This analysis of ASCEND-D and ASCEND-TD compared daprodustat to active ESAs on measures of IV iron use in dialysis patients. Method Daprodustat and ESAs were compared in patients with CKD anaemia on haemodialysis/peritoneal dialysis (ASCEND-D); haemodialysis (ASCEND-TD). ASCEND-D (N = 2,964) was an open-label CV outcome study using daprodustat once daily, while ASCEND-TD (N = 407) was a double-blind, double-dummy, 52-week study investigating three times weekly dosing of daprodustat. In both studies, following randomisation, treatment dosage was titrated to achieve the Hb target range of 10.0–11.0g/dL, with Hb efficacy assessed during the evaluation period (EP), Weeks 28–52. All patients were required to have ferritin &amp;gt;100 ng/mL and/or transferrin saturation (TSAT) &amp;gt;20% at baseline for inclusion. Throughout the study, iron therapy was administered if ferritin was ≤100 ng/mL and/or TSAT was ≤20% so patients would remain iron replete throughout the study. Investigators chose the route and dose of iron administration per patient iron status and clinical judgement. Stopping threshold criteria of 800 ng/mL ferritin + TSAT &amp;gt;20%, or TSAT&amp;gt;40% were implemented to avoid iron overload, but investigators could stop administration of iron at levels below the protocol-defined stopping thresholds. The average monthly IV iron dose (mg)/patient to Week 52 was a principal secondary endpoint, while the proportion of patients who met iron management criteria with a decrease in monthly IV iron dose during the EP relative to baseline and until patients received first transfusion were exploratory endpoints. The baseline monthly IV iron dose was defined as the average monthly IV iron (mg) over the 16 weeks prior to randomisation for ASCEND-D and over the 12 weeks prior to randomisation for ASCEND-TD. Results The proportion of patients with IV iron use at baseline was similar in both treatment arms for ASCEND-D (64%) but lower in the daprodustat group in ASCEND-TD (63% vs 72% in the ESA group). In both studies the proportion of patients receiving IV iron during the EP decreased (ASCEND-D: daprodustat 49%, ESA 52%; ASCEND-TD: daprodustat 38%, ESA 40%). The average monthly IV iron dose during the EP and from Day 1 to Week 52 was lower than monthly IV iron dose at baseline, however daprodustat was not associated with a statistically significant reduction in monthly IV iron per patient to Week 52 vs ESA comparator (Table 1). After a period of IV iron requirements decreasing, based on adjustment to protocol-specified levels, IV iron dosage remained relatively stable for daprodustat and ESA (Figure 1). In ASCEND-D, 3 of 23 pre-defined subgroups (prior ESA dose group, ESA hyporesponders2, history of myocardial infarction) showed a trend towards heterogeneity (interaction p-value &amp;lt;0.1), with differences in monthly IV iron use in the prior ESA dose group receiving ≥7000 U/week (-21.2 mg/month) and in the ESA hyporesponder group (-31.7 mg/month) in favour of daprodustat. Fewer patients met the criteria for stopping iron while on daprodustat vs ESA, whereas the converse was observed in ASCEND-TD (Table 1). Conclusion In ASCEND-D and -TD, no clinically or statistically significant reduction in monthly IV iron use was seen with daprodustat vs ESA comparators, although there was a numerical decrease in the proportion of patients receiving IV iron during the EP for the daprodustat group in both studies.

Efficacy and Safety of Roxadustat in Chinese Hemodialysis Patients: A Systematic Review and Meta-Analysis

(1) Background: Recently more and more Chinese clinical studies have been conducted to compare the efficacy and safety of roxadustat with erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. We aimed to assess the efficacy and safety of roxadustat in Chinese HD patients. (2) Methods: The PubMed, Embase, the Cochrane Library, Web of Science, WanFang, China National Knowledge Infrastructure (CNKI), SinoMed, and VIP databases were searched from their inception to July 2022 for randomized controlled trials (RCTs) that compared the efficacy and safety of roxadustat to those of ESAs in treating anemia in Chinese HD patients. (3) Results: Twenty-one RCTs involving 1408 patients were enrolled. Our study showed that the improvement of hemoglobin (Hb) levels and iron metabolism were significantly higher in the roxadustat group than in the ESA group. Additionally, the total adverse events risk was significantly lower in the roxadustat group. (4) Conclusions: In this meta-analysis, we found that roxadustat was more effective and safer than ESAs in treating anemia in Chinese HD patients.

Effect of erythropoiesis-stimulating agents on breast cancer patients: a meta-analysis.

Erythropoiesis-stimulating agents (ESAs) have been reported to increase the risk of death in cancer patients. In this study, we selected breast cancer, which is currently the most prevalent cancer worldwide, for a meta-analysis to re-examine the advantages and disadvantages of using ESAs. All relevant studies were searched by PubMed, Embase, Web of science, and Cochrane Library. Endpoints including mortality, incidence of thrombo-vascular events, hemoglobin, and transfusion requirements were meta-analyzed based on random-effects model or fixed-effect model. 10 studies were finally included, with a total sample size of 6785 patients. The risk of mortality was higher in patients using ESA than in controls (RR 1.07, 95% CI 1.01-1.13, P = 0.03); subgroup analysis found that the mortality rate was higher in patients treating with ESA for > 6months (RR 1.27, 95% CI 1.05-1.55, P = 0.01) and epoetin α (RR 1.07, 95% CI 1.01-1.14, P = 0.03). The incidence of thrombo-vascular adverse events was higher in patients using ESA than in controls (RR 1.53, 95% CI 1.27-1.86, P < 0.0001). The ESA group was more effective in improving anemia in cancer patients (MD 1.20, 95% CI 0.77-1.63, P < 0.00001). The blood transfusion needs of patients in the ESA group were significantly lower (RR 0.52, 95%CI 0.44-0.60, P < 0.00001). There was no statistically significant difference between the two groups in disease progression-related conditions (HR 1.03, 95%CI 0.95-1.12, P = 0.52). ESAs increase the risk of mortality and the incidence of thrombo-vascular adverse events in breast cancer patients, while reducing their anemia symptoms and transfusion requirements. Registration PROSPERO CRD42022330450.

Ferric Carboxymaltose and Erythropoiesis-Stimulating Agent Treatment Reduces the Rate of Blood Transfusion in Refractory Anemia.

Background: Erythropoiesis-stimulating agents (ESAs) are used to treat refractory anemia (RA). Guidelines suggest iron supplementation for unresponsive patients, regardless of iron deficiency. The primary aim of this study was to evaluate the effect of iron supplementation with ferric carboxymaltose (FCM) on the reduction of red blood cell transfusion (RBCT) rate in transfusion-dependent RA patients. Methods: This was a prospective quasi-randomized study, wherein patients were randomly assigned into three groups: (A) ESAs alone, (B) ferric gluconate (FG) and ESAs, and (C) FCM and ESAs. Hemoglobin and ferritin levels, as well as the number of RBCTs at 4 and 28 weeks were compared. Economic evaluation was also performed. Results: A total of 113 RA patients were enrolled. In total, 43 were treated with intravenous FG and ESAs, 38 with FCM and ESAs, and 32 with ESAs alone. At both follow-ups, erythropoietic response was increased in those receiving iron as compared with those with ESAs alone (p = 0.001), regardless of the type of iron. At one month, ferritin levels were higher in the FCM and ESA groups (p = 0.001). RBCTs were lower in both iron groups. The less costly treatment strategy was FCM, followed by FG, and lastly ESAs. Conclusions: Addition of iron to ESAs in RA reduced RBCT requirement and improved hemoglobin values.

MO534: Associations of Haemoglobin Values and Rate of Changes With Mace in the ASCEND-D Randomised Clinical Trial

Abstract BACKGROUND AND AIMS Preliminary analyses suggest that absolute haemoglobin (Hb) values and rapid Hb changes may be associated with adverse outcomes in patients with anaemia of chronic kidney disease (CKD) treated with erythropoiesis-stimulating agents (ESAs) [1–3]. In this exploratory post-hoc analysis of the ASCEND-D trial, we investigated the association between absolute Hb values or Hb changes over 4-week periods and the occurrence of the first adjudicated major adverse cardiovascular event (MACE) in patients with CKD on dialysis who were treated with either daprodustat or ESAs. METHOD ASCEND-D was an event-driven cardiovascular outcomes trial conducted in over 30 countries that randomized 2964 CKD patients undergoing dialysis with a baseline Hb of 8.0–11.5 g/dL to receive oral, once-daily daprodustat (1487 patients), or a conventional ESA (epoetin alfa or darbepoetin; 1477 patients). Available doses were daprodustat 1–24 mg once-daily, epoetin alfa 1500–60 000 U total weekly dose, and darbepoetin 20–400 µg total 4-weekly dose. The co-primary endpoints of non-inferiority for first occurrence of adjudicated MACE and mean Hb change from baseline to weeks 28 through 52 were met and have been reported recently [4]. MACE was a composite of death from any cause, non-fatal myocardial infarction or non-fatal stroke. An independent clinical events committee, blind to treatment assignment, adjudicated the events. To examine the association of post-randomization absolute Hb values and Hb changes with first adjudicated MACE, we divided each patient's time in the study before a first MACE or end of follow-up into distinct 4-week intervals. We then calculated a post-randomization mean Hb value and Hb rate of increase or decrease at each 4-week interval. Separately for each treatment arm, we grouped these 4-week periods into quintiles of mean Hb values and Hb rates of increase or decrease (see Table 1), and calculated MACE rates for each quintile. This analysis did not include MACE that occurred before Week 4, as this was the time for the first scheduled post-randomization Hb collection. We used the average of Hb values imputed by the multiple imputation method to impute missing Hb values. RESULTS This analysis included 361 and 389 first MACE in the daprodustat and ESA treatment groups, respectively. When evaluating rates of the first occurrence of adjudicated MACE by absolute Hb value quintiles and irrespective of Hb change (‘All’ column in Figure 1), the MACE rate was higher in the low Hb quintile than in the high Hb quintile across both treatment groups. In the evaluation of rates of the first MACE by Hb change quintile and irrespective of absolute Hb value (‘All’ row in Figure 1), rates of MACE were comparable across Hb change quintiles within each treatment group. When MACE risk was evaluated by both absolute Hb value and Hb change quintiles, the highest MACE rate was observed in the lowest Hb quintile (Q1 row) with the largest positive change (Q5 increase column), and this was more pronounced in the ESA group. CONCLUSION This exploratory analysis suggests a possible association between Hb quintile and MACE outcome for both absolute and fluxes in Hb values. However, this analysis has several limitations including a small number of events in each quintile, possible confounding by severity of disease and the choice of assessment window. Further studies are needed to confirm these findings.

Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis

BackgroundAmong 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.MethodsIn 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.ResultsA 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.ConclusionsAmong 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.)

Overview of Systematic Reviews (SRs) of Erythropoiesis-Stimulating Agents (ESAs) As Standards of Care for Non-Myeloid Cancer Patients with Chemotherapy-Induced-Anemia (CIA)

OBJECTIVES: While chemotherapy is fundamental to the treatment of many cancers, it is associated with adverse events (AEs), including anemia. CIA is linked to many symptoms, including fatigue and cognitive impairment. Most cancer patients receiving chemotherapy experience CIA. ESAs are indicated for treatment of CIA in non-myeloid cancers. Given the extensive data available, we reviewed SRs of the existing evidence on ESAs for treatment of CIA, to assess their relative efficacy and safety.METHODS: A search for published SRs of ESAs for the treatment of CIA in adults with non-myeloid cancers was conducted across seven databases and three online resources, from inception to July 2020. Data were extracted on hemoglobin-related (Hb)-outcomes; mortality; health-related quality of life (HRQoL), iron use, red blood cell (RBC) transfusions, cancer-related outcomes, and serious AEs (SAEs) including thromboembolic events. Risk of bias was assessed by two reviewers using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool.RESULTS: Of 1027 records assessed, 33 records met eligibility criteria; from these, 14 SRs (from 19 publications) were considered core and were extracted. The majority of SRs (n=13) were meta-analyses of randomized, controlled trials. Mortality was evaluated in 9 SRs: 5 reported no difference between ESA vs. control (best supportive care (BSC) and/or placebo and/or no treatment) and 2 reported higher mortality with ESA vs. control (standard care (no iron or oral iron) and/or placebo and/or no treatment). Cancer-related overall survival was not significantly different for ESA vs. control (BSC or placebo) in 2 SRs, or vs. no ESA treatment in 1 SR. Relapse-free, recurrence-free and progression-free survival did not differ between ESA vs. BSC, no treatment, or placebo, according to 1 SR.Two SRs reported a significantly improved change in Hb from baseline for ESA vs. placebo or BSC. Four SRs reported significantly improved hematological response (definitions varied by study) for ESA vs. control (BSC and/or placebo and/or no treatment) (Table). RBC transfusion requirements were reported for 5 treatment comparisons in 12 SRs. For 3 comparisons (ESA vs. control (BSC and/or placebo and/or no treatment); IV iron + ESA vs. standard care; and IV iron + ESA vs. no iron + ESA), there was a consistent statistically significant reduction in transfusion rates with ESA-based treatment. For 2 other comparisons, 1 SR reported no significant difference in transfusion rates with oral iron + ESA vs. no iron + ESA, and 2 SRs found no difference between darbepoetin vs. epoetin. ESA was associated with a requirement for significantly fewer RBC units per patient vs. control (BSC or placebo) in 1 SR.Functional Assessment of Cancer Therapy-Anemia (FACT-An, 6 SRs) and FACT-Fatigue (FACT-F, 7 SRs) were the only HRQoL measures reported. Two SRs reported clinically important improvements in FACT-An with ESA vs. control (BSC and/or placebo); the remaining SRs reported difficulty in interpreting results due to study heterogeneity. Five SRs reported significant improvements in FACT-F with ESA vs. control (BSC and/or placebo and/or no treatment). One SR did not present a meta-analysis, stating that FACT-F results did not differ for ESA vs. placebo groups, and 1 SR reported a significant improvement in FACT-F for IV iron + ESA vs. standard care (no iron or oral iron).Of 2 SRs reporting SAEs, 1 found no difference in incidence for IV iron + ESA vs. standard care (no iron or oral iron) and 1 found significantly greater incidence for ESA vs. no treatment. Of 6 SRs that compared ESA vs. control, 3 reported an increased risk of thromboembolic events with ESAs in the treatment of CIA and 2 reported no significant difference between treatment groups. The remaining SR reported numerically higher incidences of thromboembolic events with ESA vs. control (no statistical comparison).Several outcomes of interest were not reported, including time to first rescue therapy and supplementary iron use. Most SRs did not report on study quality.CONCLUSIONS: In all SRs reporting efficacy, there were improvements in Hb change from baseline, Hb response, and reduction in RBC transfusions for patients with CIA treated with ESAs vs. control. Results were less consistent across SRs for mortality, thromboembolic events, and HRQoL for ESA vs. control. Lack of study quality reporting may affect the strength of these findings. [Display omitted] DisclosuresMorga: Astellas Pharma Europe Ltd.: Current Employment. Atzinger: Astellas Pharma Inc.: Current Employment. Arber: York Health Economics Consortium Ltd: Current Employment. King: York Health Economics Consortium Ltd: Current Employment. Phalguni: York Health Economics Consortium Ltd: Current Employment. Sanderson: York Health Economics Consortium Ltd: Current Employment. Alexandre: Astellas Pharma Europe B.V.: Current Employment.

Roxadustat treatment for anemia in peritoneal dialysis patients: A randomized controlled trial

Roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, promotes erythropoiesis and regulates iron metabolism. This study investigated the efficacy and safety of roxadustat in Chinese patients with anemia on peritoneal dialysis (PD). One hundred and twenty-nine patients were randomized and treated with roxadustat (n=86) or erythropoiesis-stimulating agents (ESAs) (n=43) for 24 weeks. The primary end points were the mean hemoglobin (Hb) level at week 24, the change in average Hb levels from baseline to week 24, and the cumulative response rate throughout the treatment period. The secondary end points included changes in hepcidin and iron indices and serum lipid levels. Subgroup analysis examined the effect of inflammatory status on the efficacy of Hb. Safety was assessed as the occurrence of emergent adverse events after treatment. The mean average Hb levels at week 24 and average change in Hb levels from baseline to week 24 were 11.5g/dL and 2.5g/dL in the roxadustat group and 11.2g/dL and 2.2g/dL in the ESAs group, respectively. The cumulative response rate was 96% in the roxadustat group and 92% in the ESAs group at week 24. Roxadustat decreased hepcidin levels and increased total iron-binding capacity. The decreases in total cholesterol and low-density lipoprotein cholesterol were greater with roxadustat than with ESAs. Roxadustat-induced Hb increases were independent of baseline C-reactive protein levels. Common adverse events included hyperkalemia, hypertension, and insomnia. Roxadustat effectively corrected and maintained target Hb levels in Chinese PD patients. This trial was registered in the Chinese Clinical Trial Register (ChiCTR2000035054).

Roxadustat for the treatment of anemia in patients with chronic kidney diseases: a meta-analysis.

Background: Anemia is a common complication of chronic kidney disease (CKD). Treating renal anemia with erythropoiesis-stimulating agents (ESAs) or erythropoietin analogs is effective but has side effects. Therefore, we performed a meta-analysis to assess the efficacy and safety of roxadustat in treating CKD-induced anemia.Methods: We searched publications online and conducted a meta-analysis and calculated relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences (MD) with 95% CIs for continuous data.Results: Of 110 articles, nine were included that contained 12 data sets and 11 randomized control trials on roxadustat. In the non-dialysis-dependent (NDD) high-dose/low-dose subgroups, the change in hemoglobin (Hb) levels was significantly higher in the roxadustat group than in the placebo group (P<0.0001, P=0.001, respectively). The Hb response rate of the roxadustat is higher in the NDD subgroup than in the placebo group (P<0.00001, MD=6.92, 95% CI: 4.03, 11.89). However, in the dialysis-dependent subgroup, there was no significant difference in the change in Hb levels or the Hb response rate between the roxadustat and ESA groups. There was no change in the mortality in the roxadustat group compared to that in the placebo/ESA group. Hyperkalemia may be a side effect of roxadustat.Conclusions: Roxadustat elevated the serum Hb levels in a manner similar to that observed for ESAs. Roxadustat raised the Hb levels more significantly than the placebo and showed a higher Hb response rate than the placebo group in NDD patients. Roxadustat is a safe and effective drug for anemia in CKD patients.

Effect of blood transfusions on cognitive development in very low birth weight infants.

Objective:Preterm infants frequently receive red cell transfusions; however, the effect of transfusions on cognition is unclear. We evaluated the relationship between transfusions and cognitive outcomes in preterm infants enrolled in a randomized trial of erythropoiesis stimulating agents (ESAs).Study Design:Preterm infants were randomized to ESAs or placebo during initial hospitalization, and transfusions recorded. Children were evaluated using standard developmental tests of cognition at 18–22 months (56 ESA, 24 placebo) and 3.5–4 years (39 ESA, 14 placebo)Results:Cognitive scores at 18–22 months were inversely correlated with transfusion volume at (p=0.02). Among those receiving ≥1 transfusion, cognitive scores were significantly higher in the ESA-treated group (p=0.003). At 3.5–4 years, transfusions weren’t correlated with cognitive scores.Conclusions:In the placebo group, transfused children had lower cognitive scores than did non-transfused children at 18–22 months. In the ESA group, cognitive scores did not differ by transfusion status, suggesting ESAs provide neuroprotection.