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Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial.
Shah, A, Chester-Jones, M, Dutton, SJ, Marian, IR, Barber, VS, Griffith, DM, Singleton, J, Wray, K, James, T, Drakesmith, H, et al
British journal of anaesthesia. 2022;(2):272-282
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BACKGROUND Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear. METHODS We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L-1). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes. RESULTS Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L-1) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L-1), adjusted mean difference (10.98 g L-1; 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15). CONCLUSION A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes. CLINICAL TRIAL REGISTRATION ISRCTN13721808 (www.isrctn.com).
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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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Splanchnic-Cerebral Oxygenation Ratio Decreases during Enteral Feedings in Anemic Preterm Infants: Observations under Near-Infrared Spectroscopy.
Braski, K, Weaver-Lewis, K, Loertscher, M, Ding, Q, Sheng, X, Baserga, M
Neonatology. 2018;(1):75-80
Abstract
BACKGROUND Anemia is common in premature infants. Due to risks with red blood cell transfusions, many anemic infants are not transfused. The implications of this pathophysiologic status, especially at times of increased metabolic demand (enteral feedings), is not well understood. Near-infrared spectroscopy (NIRS) allows for the noninvasive determination of regional oxygen saturations (rSO2) in tissues such as the brain and mesentery, giving insight into their oxygen sufficiency. OBJECTIVE We tested the hypothesis that during enteral feedings very low birth weight (VLBW) infants with a hematocrit ≤28% will experience a decrease in splanchnic rSO2 and splanchnic-cerebral oxygenation ratio (SCOR). METHODS This prospective, observational, 2-centered study included VLBW infants receiving full enteral feedings with a hematocrit ≤28%. Cerebral and splanchnic rSO2 were monitored via NIRS for 24 h. Average values were calculated for periods immediately preceding, during, and after each feeding. SCOR was calculated from these values (rSO2 splanchnic/rSO2 cerebral), and data were analyzed using a linear mixed effect model. RESULTS Fifty neonates with a median gestational age of 28 weeks (range 23-32), a birth weight of 1,118 ± 284 g (mean ± SD), and a hematocrit of 26 ± 2% (mean ± SD) were studied. During feedings, SCOR decreased significantly from baseline (0.72 ± 0.17 to 0.69 ± 0.17, p = 0.043). With feedings, there was a trend of decreased splanchnic rSO2 (47 ± 11 to 45 ± 10, p = 0.057) and no change in cerebral rSO2 (66 ± 8 to 66 ± 7, p = 0.597). CONCLUSIONS VLBW infants with a hematocrit ≤28% had a decrease in SCOR and a trend towards decreased splanchnic rSO2 with enteral feedings.
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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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Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.
Aroda, VR, Edelstein, SL, Goldberg, RB, Knowler, WC, Marcovina, SM, Orchard, TJ, Bray, GA, Schade, DS, Temprosa, MG, White, NH, et al
The Journal of clinical endocrinology and metabolism. 2016;(4):1754-61
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CONTEXT Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. OBJECTIVE To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). DESIGN Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. SETTING Twenty-seven study centers in the United States. PATIENTS DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. INTERVENTION Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). MAIN OUTCOME MEASURES B12 deficiency, anemia, and peripheral neuropathy. RESULTS Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. CONCLUSIONS Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.
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Zinc supplementation improved length growth only in anemic infants in a multi-country trial of iron and zinc supplementation in South-East Asia.
Dijkhuizen, MA, Winichagoon, P, Wieringa, FT, Wasantwisut, E, Utomo, B, Ninh, NX, Hidayat, A, Berger, J
The Journal of nutrition. 2008;(10):1969-75
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Data from 4 randomized, placebo-controlled, double-blind trials in Indonesia, Thailand, and Vietnam, the South-East Asian Multicountry Trial on Iron and Zinc supplementation in Infants (SEAMTIZI), were pooled to investigate the effects of iron and zinc supplementation infant growth. Infants (n = 2451) aged 4-6 mo old were supplemented with iron (10 mg/d) and/or zinc (10 mg/d) for 6 mo. Overall, neither iron nor zinc supplementation prevented the progressive growth faltering during infancy, which is common in many developing countries. However, infants who received zinc were less likely to be stunted at the end of the supplementation period (odds ratio 0.80; 95% CI 0.64-1.0). Boys had a 30% higher risk of being stunted at the end of the study than girls (P < 0.01). Baseline factors modified the effect of supplementation, with infants anemic at baseline (hemoglobin < 105 g/L) benefiting from zinc supplementation, with an estimated increase in height-for-age Z-score (HAZ) score of 0.17 (P < 0.01), but with no effect of zinc supplementation on growth in infants not anemic at baseline. Iron supplementation negatively affected linear growth in infants with a birth weight of >3500 g (estimated effect size, -0. 14 HAZ score; P < 0.01), but with no significant effect in infants with a lower birth weight. This study shows that blanket supplementation of infants with iron or zinc will not be beneficial to all recipients and may have adverse effects in some. Hence, interventions such as iron and zinc supplementation for infants should be restricted to subgroups in which there is a clear benefit and baseline factors should be considered and characterized before implementing new policies.
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Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants.
López de Romaña, G, Cusirramos, S, López de Romaña, D, Gross, R
The Journal of nutrition. 2005;(3):646S-652S
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Anemia, micronutrient deficiencies, and growth faltering are still common in Peru. The study objective was to determine the efficacy of different micronutrient supplements in preventing growth failure, anemia, and micronutrient deficiencies in Peruvian infants. Three hundred and thirteen infants aged 6 to 12 mo participated in a double-blind, masked, controlled trial in which they were randomly assigned to receive either a daily dose of iron (DI), a daily dose of multiple micronutrients (DMM), a weekly dose of multiple micronutrients, or a placebo (P) for 6 mo. None of the supplements tested prevented growth faltering or the morbidities common during infancy. Anemia and plasma homocysteine concentrations fell significantly in all groups during the study, but the mean change of plasma homocysteine during the trial period was significantly smaller in the DI group than in other groups, and the increase in hemoglobin concentrations was smaller in the P group than the micronutrient treatment groups. Plasma ferritin concentrations decreased least in the groups taking daily micronutrient supplements containing iron (DI and DMM). There were no significant differences among groups in mean final values or changes in plasma zinc, retinol, tocopherol, or riboflavin. Although the DMM intervention was the most efficacious for preventing anemia, iron, and zinc deficiencies, 15%, 20%, and 50% of this group still remained anemic, zinc deficient, and iron deficient, respectively, at the end of the study. Further research thus should investigate whether higher doses of iron and zinc, together with infection control measures, are more efficacious.
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Mechanisms of unexplained anemia in the nursing home.
Artz, AS, Fergusson, D, Drinka, PJ, Gerald, M, Bidenbender, R, Lechich, A, Silverstone, F, McCamish, MA, Dai, J, Keller, E, et al
Journal of the American Geriatrics Society. 2004;(3):423-7
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OBJECTIVES To characterize anemia in elderly nursing home residents. DESIGN Prospective multiinstitutional cohort study. SETTING Five nursing homes. PARTICIPANTS From retrospective analysis, residents found to be anemic using chart review were prospectively randomized. Of the 81 residents enrolled, 60 were anemic. MEASUREMENTS Chart review for medical history and factors related to treatment or history of anemia, extensive laboratory evaluation for causes of anemia, and classification of anemia by two hematologists. RESULTS Among the 60 anemic residents, the causes of anemia were idiopathic (n=27), iron-deficiency (n=14), anemia associated with chronic disease (n=8), anemia of renal insufficiency (n=6), and other (n=5). The eryrthropoietin (EPO) response to anemia was lower in residents with idiopathic anemia (IA) than in those with iron-deficiency anemia, and this correlated with renal function as estimated using calculated creatinine clearance. In this elderly population, advancing age was not correlated with lower EPO response. CONCLUSION IA is common in nursing home residents. A lower EPO response contributes to the high prevalence of anemia in this setting and may be due, in part, to occult renal dysfunction.