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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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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 effect of anaemia on normal tissue toxicity and survival outcomes in prostate cancer treated with radical radiotherapy and neo-adjuvant androgen deprivation.
Keenan, LG, Ibrahim, N, Dunne, MT, Finn, M, Armstrong, JG
The British journal of radiology. 2020;(1108):20190577
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OBJECTIVE It has been established that survival and toxicity outcomes in some cancer types could be influenced by haemoglobin (Hb) levels. This study aims to determine if pre-treatment Hb is associated with late toxicity or survival outcomes in prostate cancer. METHODS Data from one Phase III randomised controlled trial and one single arm translational trial were analysed. Patients had localized prostate cancer and received ≥70 Gy radiotherapy and neo-adjuvant androgen deprivation between 1997 and 2013. RESULTS 302 males were included. Median follow-up was 6.8 years for toxicity and 10.3 years for survival outcomes. Patients with Hb below the reference range were more likely to experience Grade 2-3 late gastrointestinal toxicity than patients with Hb within the range (p = 0.050). Neither late genitourinary toxicity, erectile function toxicity, prostate-specific antigen relapse free survival nor overall survival of patients were statistically significantly different between groups. CONCLUSION Anaemia in prostate cancer is found in the minority of patients and is usually mild. Prostate cancer patients undergoing radiotherapy with low Hb were more likely to experience Grade 2-3 late gastrointestinal toxicity. ADVANCES IN KNOWLEDGE This study is one of the first in the published literature to investigate the role of Hb in prostate cancer toxicity and survival. We have found an association between Hb below the reference range and late GI toxicity. Consideration should be given to further investigating patients with iron deficiency anaemia to guide management options and outrule underlying GI pathology before proceeding with radiotherapy treatment.
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A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis.
Akizawa, T, Yamaguchi, Y, Otsuka, T, Reusch, M
Nephron. 2020;(8):372-382
Abstract
INTRODUCTION Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD). OBJECTIVE Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan. METHODS Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study. RESULTS Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events. CONCLUSION Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.
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Establishing Ghanaian adult reference intervals for hematological parameters controlling for latent anemia and inflammation.
Bawua, ASA, Ichihara, K, Keatley, R, Arko-Mensah, J, Dei-Adomakoh, Y, Ayeh-Kumi, PF, Erasmus, R, Fobil, J
International journal of laboratory hematology. 2020;(6):705-717
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BACKGROUND In Ghana, diagnostic laboratories rely on reference intervals (RIs) provided by manufacturers of laboratory analyzers which may not be appropriate. This study aimed to establish RIs for hematological parameters in adult Ghanaian population. METHODS This cross-sectional study recruited 501 apparently healthy adults from two major urban areas in Ghana based on the protocol by IFCC Committee for Reference Intervals and Decision Limits. Whole blood was tested for complete blood count (CBC) by Sysmex XN-1000 analyzer, sera were tested for iron and ferritin by Beckman-Coulter/AU480, for transferrin, vitamin-B12, and folate was measured by Centaur-XP/Siemen. Partitioning of reference values by sex and age was guided by "effect size" of between-subgroup differences defined as standard deviation ratio (SDR) based on ANOVA. RIs were derived using parametric method with application of latent abnormal values exclusion method (LAVE), a multifaceted method of detecting subjects with abnormal results in related parameters. RESULTS Using SDR ≥ 0.4 as a threshold, RIs were partitioned by sex for platelet, erythrocyte parameters except mean corpuscular constants, and iron markers. Application of LAVE had prominent effect on RIs for majority of erythrocyte and iron parameters. Global comparison of Ghanaian RIs revealed lower-side shift of RIs for leukocyte and neutrophil counts, female hemoglobin and male platelet count, especially compared to non-African countries. CONCLUSION The LAVE effect on many hematological RIs indicates the need for deliberate secondary exclusion for proper derivation of RIs. Obvious differences in Ghanaian RIs compared to other countries underscore the importance of country-specific RIs for improved clinical decision-making.
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Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study.
Rostoker, G, Loridon, C, Griuncelli, M, Rabaté, C, Lepeytre, F, Ureña-Torres, P, Issad, B, Ghali, N, Cohen, Y
EBioMedicine. 2019;:461-471
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis. METHODS Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy. FINDINGS PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5-14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27-11%)) or mild iron overload (PDFF: 5% (0.30-11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 μmol/g, final 160 μmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 μmol/g, final: 45 μmol/g; P = 0.002). INTERPRETATION Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients. TRIAL REGISTRATION NUMBER (ISRCTN): 80100088.
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Impact of preoperative anemia on outcomes in patients undergoing curative resection for gastric cancer: a single-institution retrospective analysis of 2163 Chinese patients.
Liu, X, Qiu, H, Huang, Y, Xu, D, Li, W, Li, Y, Chen, Y, Zhou, Z, Sun, X
Cancer medicine. 2018;(2):360-369
Abstract
We sought to evaluate whether preoperative anemia was an important determinant of survival in gastric cancer (GC). A single institution cohort of 2163 GC patients who underwent curative resection were retrospectively analyzed. Anemia was defined as a preoperative hemoglobin level <120 g/L in males and <110 g/L in females. Overall survival (OS) was analyzed using the Kaplan-Meier method, and a multivariate Cox proportional hazards model was performed to identify the independent prognostic factor. Anemic patients had a poorer OS compared with nonanemic patients after resection for tumor-nodes-metastasis (TNM) stage III tumors (5-year OS rate: 32.2% vs. 45.7%, P < 0.001) but not stage I (P = 0.480) or stage II (P = 0.917) tumors. Multivariate analysis revealed that preoperative anemia was an independent prognostic factor in TNM stage III (hazard ratio [HR], 1.771; 95% CI, 1.040-3.015; P = 0.035). In a stage-stratified analysis, preoperative anemia was still independently associated with OS in TNM stages IIIa through IIIc (P < 0.001, P = 0.075, and P = 0.012, respectively), though the association was only marginal in stage IIIb. Of note, preoperative mild anemia had a similar prognostic value in TNM stage III GC. Furthermore, preoperative anemia was significantly associated with more perioperative transfusions, postoperative complications and several nutritional-based indices, including the prognostic nutritional index (PNI), preoperative weight loss and performance status (all P < 0.05). Preoperative anemia, even mild anemia, was an important predictor of postoperative survival for TNM stage III GC.
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Effect of Zinc Acetate Dihydrate (NobelzinR) Treatment on Anemia and Taste Disorders in Patients with Chronic Kidney Disease with Hypozincemia.
Sato, D, Gohda, T, Kihara, M, Kanaguchi, Y, Kobayashi, T, Mano, S, Sasaki, Y, Nohara, N, Murakoshi, M, Nakata, J, et al
Acta medica Okayama. 2018;(5):535-538
Abstract
Some patients with chronic kidney disease (CKD) receiving hemodialysis develop erythropoietin-resistant anemia, possibly due to zinc deficiency. The frequency of zinc deficiency in CKD (stages 1-5 and 5D) and CKD improvement via zinc supplementation are not completely verified. Here 500 CKD patients (Stage 1/2, n=100; Stage 3, n=100; Stage 4, n=100, Stage n=5, 100; Stage 5D, n=100) will be recruited to determine the frequency of serum zinc deficiency at each CKD stage. Patients with serum zinc concentrations <80 μg/dL will be treated with zinc acetate dihydrate (NobelzinR) to evaluate its effects on hypozincemia, taste disturbances, and anemia.
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Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.
Provenzano, R, Besarab, A, Wright, S, Dua, S, Zeig, S, Nguyen, P, Poole, L, Saikali, KG, Saha, G, Hemmerich, S, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016;(6):912-24
Abstract
BACKGROUND Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. STUDY DESIGN Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. SETTING & PARTICIPANTS Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. INTERVENTION Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. OUTCOMES Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). MEASUREMENTS Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). RESULTS Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. LIMITATIONS Short treatment duration and small sample size. CONCLUSIONS In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.
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Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
Johansson, PI, Rasmussen, AS, Thomsen, LL
Vox sanguinis. 2015;(3):257-66
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BACKGROUND AND OBJECTIVES This trial explores whether intravenous iron isomaltoside 1000 (Monofer®) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery. STUDY DESIGN AND METHODS The trial is a prospective, double-blind, comparative, placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery. The patients were randomized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo. RESULTS Mean preoperative haemoglobin in the active treatment group was 14·3 g/dl vs. 14·0 g/dl in the placebo group. At discharge 5 days after surgery, haemoglobin levels were reduced to 10·7 and 10·5 g/dl, respectively. One month after surgery, haemoglobin concentration had increased to an average of 12·6 g/dl vs. 11·8 g/dl (p = 0·012) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group (38·5% vs. 8·0%; p = 0·019). There were no differences in side-effects between the groups. CONCLUSION A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery, with a short-term safety profile similar to placebo. Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed.
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Extended prophylaxis with nevirapine and cotrimoxazole among HIV-exposed uninfected infants is well tolerated.
Aizire, J, Fowler, MG, Wang, J, Shetty, AK, Stranix-Chibanda, L, Kamateeka, M, Brown, ER, Bolton, SG, Musoke, PM, Coovadia, H
AIDS (London, England). 2012;(3):325-33
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OBJECTIVE Nevirapine and cotrimoxazole are associated with hematologic toxicities and skin-rash. Safety of their concurrent use for prophylaxis over extended periods among HIV-exposed uninfected infants has not been previously assessed. DESIGN Secondary data analysis of the 'HIV Prevention Trials Network-046 protocol' (version 2.0), a phase-III, randomized, placebo-controlled trial that assessed efficacy and safety of nevirapine prophylaxis against breast milk transmission of HIV-1. METHODS Trial infants received 6-month study nevirapine/placebo, and standard-of-care peripartum single-dose nevirapine+/- zidovudine 'tail', and cotrimoxazole prophylaxis from 6 weeks through breastfeeding cessation. Adverse events were monitored using United States Division of AIDS Toxicity Tables (2004). Risk of neutropenia, anemia and skin-rash in the cotrimoxazole + nevirapine and the cotrimoxazole + placebo groups were compared using negative-binomial regression. RESULTS Incidence of neutropenia and/or anemia, and skin-rash was highest during the first 6 weeks of life and declined, thereafter, regardless of study group. Time to first adverse event after 6 weeks was similar in cotrimoxazole + nevirapine and cotrimoxazole + placebo groups: hazard ratio (95% confidence interval) was 1.26 (0.96-1.66) for neutropenia and/or anemia (all grades), 1.27 (0.80-2.03) for neutropenia and/or anemia (grade ≥3) and 1.16 (0.46-2.90) for skin-rash (grade ≥2). There were no statistically significant differences in immediate (6 weeks-6 months) and long-term (6-12 months) adverse event risk among infants on cotrimoxazole + nevirapine versus cotrimoxazole + placebo. CONCLUSION Extended nevirapine and cotrimoxazole prophylaxis through 6 months of age among HIV-exposed uninfected infants did not appear to increase the immediate or long-term risk of neutropenia, anemia or skin-rash. Concurrent use beyond 6 months, however, needs to be evaluated.