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Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial.
Nangaku, M, Hamano, T, Akizawa, T, Tsubakihara, Y, Nagai, R, Okuda, N, Kurata, K, Nagakubo, T, Jones, NP, Endo, Y, et al
American journal of nephrology. 2021;(1):26-35
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Abstract
BACKGROUND Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. METHODS Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients and 25-250 μg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40-52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. RESULTS Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9 g/dL for CERA (n = 109; 95% CI 11.7-12.0); the difference between the groups was 0.1 g/dL (95% CI -0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of -1.0 g/dL. The mean hemoglobin level was within the target range (11.0-13.0 g/dL) during weeks 40-52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. CONCLUSIONS Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.
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The effects of enteral artificial amniotic fluid-containing erythropoietin on short term outcomes of preterm infants.
Hosseini, M, Azampour, H, Raeisi, S, Behtari, M, Valizadeh, H, Saboohi, R
The Turkish journal of pediatrics. 2019;(3):392-398
Abstract
Hosseini M, Azampour H, Raeisi S, Behtari M, Valizadeh H, Saboohi R. The effects of enteral artificial amniotic fluid-containing erythropoietin on short term outcomes of preterm infants. Turk J Pediatr 2019; 61: 392-398. Necrotizing Enterocolitis (NEC) is a common devastating gastrointestinal disease, which usually develops in premature infants. Erythropoietin (EPO) as a hematopoietic hormone produced by the kidney can also be naturally found in amniotic fluid and breast milk. There is some evidence that supports the contribution of EPO in the prevention of inflammation and intestinal tissue repair. This study was aimed to determine if oral administration of artificial amniotic fluid with or without EPO would protect preterm infants against NEC and improve the certain neonatal outcomes. In this study, 150 preterm infants with gestational age 28 weeks or less and birth weight 1250 grams or less were enrolled. The infants were divided randomly into 3 groups: 1) Control group (n=50) with routine feeding protocol without any administration; 2) Amniotic fluid group (n=50) with 5mL/kg synthetic amniotic fluid; 3) EPO group (n=50) with RhuEPO dissolved in the synthetic amniotic fluid. The administrations of the study solution were started 3 days after the birth and were continued for 3 weeks (21 days). The infants in the study groups were followed up until discharge and the frequency of NEC, mortality, and other complications of the disease among the groups were compared. The mortality rate in preterm infants of the amniotic fluid and EPO groups were significantly lower than in the control group (p=0.027). We couldn`t find any significant differences in the frequency of NEC and other complications among the three study groups. The administration of synthetic amniotic fluid (with or without EPO) in preterm infants may decrease the mortality rate. Use of EPO in synthetic amniotic fluid did not affect the frequency of NEC.
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Erythropoietin and ferritin response in native highlanders aged 4-19 years from the Leh-Ladakh region of India.
Yanamandra, U, Senee, H, Yanamadra, S, Das, SK, Bhattachar, SA, Das, R, Kumar, S, Malhotra, P, Varma, S, Varma, N, et al
British journal of haematology. 2019;(2):263-268
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Abstract
The pivotal role of erythropoietin (EPO) in hypoxic adaptation has led to various studies assessing the EPO and ferritin response in native highlanders from Andes and Tibet. We assessed the relationship between EPO, haemoglobin and ferritin in 335 native highlanders (172 boys and 163 girls, aged 4 to 19 years) from Leh-Ladakh, India, who had no history of travel to lowland areas. Complete blood counts, serum EPO and ferritin levels were measured. We stratified study subjects based on age, gender, pubertal status and analysed the EPO and ferritin levels between the stratified groups respectively. The mean EPO level in boys was lower than girls. The mean ferritin level in boys was significantly higher (P = 0·013) than in girls. There was no significant variation in the EPO and ferritin levels amongst the various age groups in our study. Near normal EPO levels since childhood with a negative correlation with haemoglobin is suggestive of a robust adaptive mechanism to high altitude from the early years of life. Low ferritin levels are indicative of decreased iron stores in these native highlanders.
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Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study.
Locatelli, F, Andrulli, S, Viganò, SM, Concetti, M, Urbini, S, Giacchino, F, Broccoli, R, Aucella, F, Cossu, M, Conti, P, et al
Blood purification. 2017;(4):338-345
Abstract
BACKGROUND Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. METHODS This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. RESULTS Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29). CONCLUSIONS The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.
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Do two intravenous iron sucrose preparations have the same efficacy?
Rottembourg, J, Kadri, A, Leonard, E, Dansaert, A, Lafuma, A
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2011;(10):3262-7
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BACKGROUND Intravenous (i.v.) iron sucrose similar (ISS) preparations are available but clinical comparisons with the originator iron sucrose (IS) are lacking. METHODS The impact of switching from IS to ISS on anaemia and iron parameters was assessed in a sequential observational study comparing two periods of 27 weeks each in 75 stable haemodialysis (HD) patients receiving i.v. iron weekly and an i.v. erythropoiesis-stimulating agent (ESA) once every 2 weeks. Patients received IS in the first period (P1) and ISS in the second period (P2). RESULTS Mean haemoglobin value was 11.78 ± 0.99 g/dL during P1 and 11.48 ± 0.98 g/dL during P2 (P = 0.01). Mean serum ferritin was similar for both treatment periods (P1, 534 ± 328 μg/L; P2, 495 ± 280 μg/L, P = 0.25) but mean TSAT during P1 (49.3 ± 10.9%) was significantly higher than during P2 (24.5 ± 9.4%, P <0.0001). The mean dose of i.v. iron per patient per week was 45.58 ± 32.55 mg in P1 and 61.36 ± 30.98 mg in P2 (+34.6%), while the mean ESA dose was 0.58 ± 0.52 and 0.66 ± 0.64 μg/kg/week, respectively (+13.8%). Total mean anaemia drug costs increased in P2 by 11.9% compared to P1. CONCLUSIONS The switch from the originator IS to an ISS preparation led to destabilization of a well-controlled population of HD patients and incurred an increase in total anaemia drug costs. Prospective comparative clinical studies are required to prove that ISS are as efficacious and safe as the originator i.v. IS.
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Serum albumin is strongly associated with erythropoietin sensitivity in hemodialysis patients.
Agarwal, R, Davis, JL, Smith, L
Clinical journal of the American Society of Nephrology : CJASN. 2008;(1):98-104
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BACKGROUND AND OBJECTIVES In hemodialysis patients, the hematological response to erythropoietin (epo) is variable and clinical factors that explain this variability are incompletely understood. We tested the hypothesis that the variability in hemoglobin (Hgb) response (epo sensitivity) is determined by key nutritional, inflammation, and oxidative stress markers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Eighty-two consecutive patients on hemodialysis had 3 consecutive monthly predialysis evaluations of Hgb, total white blood cell (WBC) count, serum albumin, malondialdehyde (MDA), and monocyte chemoattractant protein-1 (MCP1). We analyzed the time course of Hgb in relationship to serum albumin, WBC, MDA, MCP1, epo and iron administration, and tests of iron sufficiency in a linear growth curve model. RESULTS Subjects with higher Hgb had a fall in Hgb and vice versa, regressing to a mean Hgb (SD) of 11.8 g/dl (1.8 g/dl). Whereas the average slope of Hgb was flat, the SD of slopes was 0.63 g/dl, which explained 39% of the variance in Hgb. Nonuse of epo was associated with a mean Hgb change of -0.18 g/dl (95% confidence interval [CI] -0.26 to -0.10) per 10,000 IU epo/mo (P < 0.05). Epo use was associated with steeper rate of change at 0.04 g/dl per mo per 10,000 IU (95% CI 0.01 to 0.07) (P < 0.01). Hgb at baseline was 0.73 g/dl higher for each 1-g/dl increase in albumin, and the rate of change increased by 0.49 g/dl per mo for each 1-g/dl increase in albumin concentration. WBC, MDA, or MCP1 had no role in predicting the baseline Hgb or its change over time. CONCLUSIONS Serum albumin concentration is an important predictor of both baseline Hgb and epo sensitivity in chronic hemodialysis patients. Factors that improve serum albumin may also improve Hgb in hemodialysis patients.
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Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment.
Mystakidou, K, Kalaidopoulou, O, Katsouda, E, Parpa, E, Kouskouni, E, Chondros, C, Tsiatas, ML, Vlahos, L
Anticancer research. 2005;(5):3495-500
Abstract
OBJECTIVE To evaluate the effectiveness and improvement in quality of life (QOL) of epoetin alfa administration supplemented with oral iron as a therapeutic regimen for patients with solid malignancies and anemia of chronic disease (ACD), not receiving chemotherapy and/or radiotherapy. PATIENTS AND METHODS A total of 100 patients with cancer-related anemia, not subjected to chemotherapy and/or radiotherapy, were randomized to receive for a maximum of 24 weeks either oral iron, equivalent to 200 mg elemental iron once daily, or epoetin alfa 40,000 IU subcutaneously once weekly plus oral iron once daily. RESULTS Patients in the epoetin alfa group had, from baseline to study end, a mean increase in hemoglobin (Hb) levels of 2.4 g/dL, whereas in the control group the mean Hb level decreased by 0.1 g/dL, (p<0.001). Improvement in QOL as assessed by the LASA and the FACT-An questionnaire were greater in patients in the epoetin alfa group than in the control group (mean change, LASA-energy level: 30.4 mm vs. 0.4 mm, -daily activities: 31.7 mm vs. 0.4 mm, -overall well-being. 32.4 mm vs. 4.9, FACT-An: 43.3 vs. 13.4, respectively). As for ECOG score, patients in the epoetin alfa group had a mean improvement of 0.16 from baseline to study end (control group: 0.06). Improvement in QOL parameters and in ECOG scores correlated positively with increased hemoglobin levels. CONCLUSION Our results suggest that weekly epoetin alfa therapy supplemented with daily oral iron increases Hb levels and improves QOL in patients with solid malignancies and ACD who are not receiving chemotherapy and/or radiotherapy. This regimen offers optimal therapy in this population taking into consideration physician's convenience and patient's compliance.
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A new dose-intense epoetin alfa regimen effective in anemic cancer patients receiving chemotherapy: an open-label, non randomized, pilot study.
Santini, D, Vincenzi, B, La Cesa, A, Virzi, V, Navajas, F, Malafarina, V, Dicuonzo, G, Cassandro, R, Esposito, V, Montesarchio, V, et al
Anticancer research. 2005;(1B):669-74
Abstract
BACKGROUND Chronic anemia is a well-recognized complication of both cancer and cytotoxic treatments and is associated with symptoms (e.g., fatigue, dyspnea) that may induce or exacerbate functional deterioration. The use of recombinant human erythropoetin (rHuEPO epoetin alfa) clearly increased haemoglobin (Hb) levels, decreased transfusion needs and allowed recovery of quality of life in anemic cancer patients (pts) undergoing chemotherapy (CT). The purpose of this open-label, non randomized, pilot study was to assess the safety and efficacy of an intensive 19-day epoetin alfa treatment in anemic patients with solid tumors receiving chemotherapy. TREATMENT patients received a single induction s.c. dose of epoetin alfa 40,000 IU day 1 and twice a dose of 10,000 IU s.c. (8.00 a.m.- 8:00 p.m.) on days 3, 5, 8, 10, 12, 15, 17 and 19. The total dose of epoetin alfa per patient was 200, 000 IU. Iron supplementation: 125 mg i.v. days and 8. Soluble transferrin receptor (sTfR) levels were performed on days 1,8 and 15. This epoetin induction regimen was not followed by an epoetin maintenance therapy. PATIENTS Twenty-nine anemic (Hb< or =11.5 g/dL) pts with non myeloid malignancies undergoing CT were included in the study. RESULTS At baseline the mean Hb level was 9.41 g/dl. On day 8, the mean Hb level increased to 10.07 g/dl (p<0.0001), reaching 10.68 g/dl on day 15 (p<0.0001). On days 22 and 29, the mean Hb levels increased to 10.93 and 11.05 g/dl, (p=0.002 and 0.033, respectively). No patient received blood transfusions. The global mean increase of Hb level was 1.64 g/dl (basal to d 29). It was defined as a major response: an increase of Hb levels > 1.5 g/dl. A rate of 62% (18/29 patients) of major responses was observed on day 21. Moreover, 25/29 patients (86.2%) presented an increase of Hb levels > 1 g/dl after 21 days. On days 8 and 15, the mean sTfR levels had increased significantly ( p=0.021 and 0.001, respectively). The increase of mean sTfR level after 15 days correlated significantly with the increase of mean Hb level in the first two weeks of epoetin therapy (p=0.05). Epoetin alfa has been well tolerated so far in the study. CONCLUSION The results of the present study suggest that an induction dose of 40,000 IU of epoetin alfa, followed by 8 maintenance doses of 20,000 IU each, may improve the standard response in terms of both time to response and Hb increase. Moreover, the Hb levels seemed to increase after epoetin therapy discontinuation (d22-29).
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Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: Effects on survival, metabolism, and function.
Lundholm, K, Daneryd, P, Bosaeus, I, Körner, U, Lindholm, E
Cancer. 2004;(9):1967-77
Abstract
BACKGROUND The role of nutrition in the palliative treatment of patients with malignancy-related cachexia is unclear. The goal of the current study was to determine whether specialized, nutrition-focused patient care could improve integrated whole-body metabolism and functional outcome in unselected weight-losing patients with malignant disease who were receiving systemic antiinflammatory (cyclooxygenase [COX]-inhibitory) treatment along with erythropoietin (EPO) support. METHODS Three hundred nine patients with malignant disease who experienced progressive cachexia due to solid tumors (primarily gastrointestinal lesions) were randomized to receive a COX inhibitor (indomethacin, 50 mg twice daily) and EPO (15-40,000 units per week) along with specialized, nutrition-focused patient care (oral nutritional support and home total parenteral nutrition [TPN]) provided on a patient-by-patient basis to attenuate inflammation, prevent anemia, and improve nutritional status. Control patients received the same indomethacin and EPO doses that study patients received without the added nutritional support. All patients were treated and followed until death. Biochemical assays (blood, liver, kidney, and thyroid), nutritional state assessment (food intake and body composition), and exercise testing with simultaneous measurement of whole-body respiratory gas exchange before and during exercise were performed before the start of treatment and then at regular intervals during the treatment period (every 2-30 months after treatment initiation). Statistical analyses were performed on 'intention-to-treat' and 'as-treated' bases. RESULTS Home TPN was provided to approximately 50% of the study patients without severe complications. Over the entire observation period, rhEPO prevented the development of anemia in both study patients and control patients. Intention-to-treat analysis revealed an improvement in energy balance for nutritionally supported patients (P < 0.03); no other significant differences in outcome between study patients and control patients were observed. As-treated analysis demonstrated that patients receiving nutrition experienced prolonged survival (P < 0.01), which was accompanied by improved energy balance (P < 0.001), increasing body fat (P < 0.05), and a greater maximum exercise capacity (P < 0.04). A trend toward increased metabolic efficiency at maximum exercise (P < 0.06) for study patients relative to control patients also was observed. CONCLUSIONS The results of the current study strongly support that nutrition is a limiting factor influencing survival and that nutritional support protects integrated metabolism and metabolic function in patients with progressive cachexia secondary to malignant disease.
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Does recombinant human erythropoietin accelerate correction of post-ulcer-bleeding anaemia? A pilot study.
Ladas, SD, Polymeros, D, Pagonis, T, Triantafyllou, K, Paspatis, G, Hatziargiriou, M, Raptis, SA
World journal of gastroenterology. 2004;(4):586-9
Abstract
AIM: Anaemia caused by acute upper gastrointestinal bleeding is treated with blood transfusion or iron, but patients usually face a two-month recovery period from post-haemorrhage anaemia. This prospective, randomised, open, pilot study was designed to investigate whether recombinant human erythropoietin (Epoetin) therapy accelerate haematocrit increase in the post-bleeding recovery period. METHODS We studied hospitalised patients admitted because of acute ulcer bleeding or haemorrhagic gastritis, who had a haematocrit of 27-33% and did not receive blood transfusions. One day after the endoscopic confirmation of cessation of bleeding, they were randomised either to erythropoietin (20 000 IU Epoetin alfa subcutaneously, on days 0, 4 and 6) plus iron (100 mg im, on days 1- 6, (G(1)) or iron only (G(2)). Haematocrit was measured on days 0, 6, 14, 30, 45, and 60, respectively. RESULTS One patient from G(1) and two from G(2) were lost to follow-up. Therefore, 14 and 13 patients from G(1) and G(2) respectively were analysed. Demographic characteristics, serum iron, ferritin, total iron binding capacity, reticulocytes, and haematocrit were not significantly different at entry to the study. Median reticulocyte counts were significantly different between groups on day six (G(1): 4.0, 3.0-6.4 vs G(2): 3.5, 2.1-4.4%, P=0.03) and median haematocrit on day fourteen [G(1): 35.9, 30.7-41.0 vs G(2): 32.5, 29.5-37.0% (median, range), P=0.04]. CONCLUSION Erythropoietin administration significantly accelerates correction of anemia after acute ulcer bleeding. The haematocrit gain is equivalent to one unit of transfused blood two weeks after the bleeding episode.