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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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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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Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial.
Richards, T, Baikady, RR, Clevenger, B, Butcher, A, Abeysiri, S, Chau, M, Macdougall, IC, Murphy, G, Swinson, R, Collier, T, et al
Lancet (London, England). 2020;(10259):1353-1361
Abstract
BACKGROUND Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes. METHODS In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants. FINDINGS Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints. INTERPRETATION Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery. FUNDING UK National Institute of Health Research Health Technology Assessment Program.
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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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Associations between intestinal parasitic infections, anaemia, and diarrhoea among school aged children, and the impact of hand-washing and nail clipping.
Mahmud, MA, Spigt, M, Bezabih, AM, Dinant, GJ, Velasco, RB
BMC research notes. 2020;(1):1
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OBJECTIVE In marginalized setting, under-nutrition and illnesses due to infectious agents create a vicious circle. In our previous study, we reported that easy-to-do hand hygiene interventions were effective in preventing intestinal parasite infections (IPIs) and reduce the rate of anaemia among school-aged children. The aim of this study was to assess the pattern of associations between IPIs, anaemia and diarrhoea among the school-aged children and to explore if the observed impact of hand-washing and nail clipping interventions in our findings was similar across children with different baseline demographic and disease characteristics. The study was based on the analysis of data that was collected during the randomized controlled trial and hence have used the same study participants and study area. RESULTS Children with IPIs had a much higher chance of also being anaemic (AOR 2.09, 95% CI 1.15-3.80), having diarrhoea (AOR 2.83, 95% CI 1.57-5.09), and vice versa. Anaemia and diarrhoea were very strongly related (AOR 9.62, 95% CI 5.18-17.85). Overall, hand-washing with soap at key times and weekly nail clipping were efficacious in preventing intestinal parasite re-infection among children despite the differences in baseline demographic characteristics. TRIAL REGISTRATION NCT01619254 (June 09/2012).
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[Effect of Qingshen Granules on inflammation/hepcidin axis and iron metabolism in patients with renal anemia: a single-center, randomized controlled trial].
Zhang, L, Wang, Y, Jin, H, Wang, D, Wei, L, Ren, K, Mao, Y
Nan fang yi ke da xue xue bao = Journal of Southern Medical University. 2019;(10):1155-1159
Abstract
OBJECTIVE To evaluate the therapeutic effect of Qingshen Granules on renal anemia in patients with damp-heat syndrome and explore the mechanisms in light of inflammation/hepcidin axis and iron metabolism. METHODS Sixty patients with renal anemia and dampness-heat syndrome were randomized into control group (n=30) and treatment group (n=30). All the patients were given routine treatment, and the patients in the treatment group received additional treatment with Qingshen Granules (3 times a day). After 12 weeks of treatments, the patients were examined for changes in the integral value of TCM syndrome, serum creatinine (Scr), glomerular filtration rate (eGFR), hemoglobin (HGB), hematocrit (HCT), red blood cell (RBC) count, interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), ferritin, growth differentiation factor-15 (GDF-15), serum iron (SI), total iron binding capacity (TIBC), transferrin saturation (TAST), soluble transferrin receptor (sTfR) and ferritin levels. RESULTS After the treatment, the scores of TCM syndrome were significantly improved in the treatment group and were better than those in the control group (P=0.000). Scr and eGFR were improved in both groups after the treatment. The levels of HGB, HCT and RBC were all improved in the two groups after treatment, and the improvements were more obvious in the treatment group (P=0.002, 0.002, and 0.017, respectively). The levels of IL-6, hs-CRP, hepcidine and GDF-15 were all lowered in the two groups after the treatment, and they were all significantly lower in the treatment group than in the control group (all P=0.000). The treatments increased the levels of SI and TAST in both of the groups, and compared with those in control group, the levels of TIBC, sTfR and ferritin were significantly lowered in the treatment group after the 12-week treatment (P=0.000). CONCLUSIONS Qingshen granules can effectively improve renal anemia in patients with damp-heat syndrome possibly by improving iron metabolism through alleviation of inflammation and reduction of hepcidine level.
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Including 60 mg Elemental Iron in a Multiple Micronutrient Supplement Blunts the Increase in Serum Zinc after 12 Weeks of Daily Supplementation in Predominantly Anemic, Nonpregnant Cambodian Women of Reproductive Age.
Holmes, JB, Kroeun, H, Houghton, LA, Gibson, RS, Harding, KB, De-Regil, LM, Kraemer, K, Barr, SI, Karakochuk, CD
The Journal of nutrition. 2019;(9):1503-1510
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BACKGROUND Multiple micronutrient (MMN) supplementation may result in interaction effects due to competing absorptive pathways of trace elements. OBJECTIVES The aim of this study was to investigate the effect of MMN supplementation with or without iron on serum zinc, selenium, and copper concentrations in Cambodian women. METHODS In a 2 × 2 factorial double-blind randomized 12-wk trial, predominantly anemic, nonpregnant women (aged 18-45 y) received daily 60 mg of iron (Fe; n = 201); 14 other micronutrients including zinc (15 mg), selenium (65 μg), and copper (2 mg), but no iron (MMN; n = 202); 60 mg iron plus MMN (Fe + MMN; n = 206); or a placebo (n = 200). Fasting morning blood was collected at baseline and 12 wk from women in 26 villages in Kampong Chhnang province. Serum zinc, selenium, and copper concentrations (secondary outcomes of the randomized controlled trial) were measured using inductively coupled plasma mass spectrometry. Generalized linear regression was used to estimate intervention effects [β coefficient (95% CI)] for Fe (with or without MMN) and MMN (with or without Fe) after testing for the presence of an Fe × MMN interaction. RESULTS A total of 760 women completed the trial. Zinc deficiency prevalence at baseline was 45% (inflammation-adjusted serum zinc <10.7 μmol/L). A significant Fe × MMN interaction (P = 0.02) was detected in the 2 × 2 analysis with serum zinc concentration as the outcome: the MMN group had a higher mean serum zinc concentration at 12 wk (12.3 μmol/L; 95% CI: 12.2, 12.4 μmol/L) compared with all other groups, and the Fe + MMN group had a higher mean serum zinc concentration (11.6 μmol/L; 95% CI: 11.5, 11.7 μmol/L) compared with the Fe group (11.0 μmol/L; 95% CI: 10.9, 11.0 μmol/L) and the placebo group (11.2 μmol/L; 95% CI: 11.1, 11.4 μmol/L). CONCLUSIONS The inclusion of 60 mg iron in the daily MMN formulation may be interfering with the absorption and/or metabolism of supplemental zinc in Cambodian women. This is of particular concern when MMN supplementation is implemented in populations with risk of zinc deficiency. This trial was registered at clinicaltrials.gov as NCT-02481375.
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Combined erythropoietin and iron therapy for anaemic patients undergoing transcatheter aortic valve implantation: the EPICURE randomised clinical trial.
Urena, M, Del Trigo, M, Altisent, OA, Campelo-Prada, F, Regueiro, A, DeLarochellière, R, Doyle, D, Mohammadi, S, Paradis, JM, Dagenais, F, et al
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2017;(1):44-52
Abstract
AIMS: The aim of this study was to evaluate, in anaemic patients, the efficacy of erythropoietin (EPO) in reducing red cell (RC) transfusion rates post TAVI. METHODS AND RESULTS This was a randomised double-blind trial. Patients with severe symptomatic aortic stenosis and concomitant anaemia with an indication for TAVI were randomised (1:1) to receive two weight-based doses of EPO (darbepoetin alfa)+iron or placebo at days 10 (±4 days) and 1 (±1 day) pre TAVI. The primary outcome was the rate of RC transfusions at 30 days. A total of 100 patients (mean age 81±7 years, male 49%) were included: 48 patients received EPO (+iron) and 52 patients received placebo. Baseline characteristics and procedural findings were well balanced between groups except for baseline haemoglobin levels, which were lower in those patients receiving EPO (10.7±1.2 vs. 11.3±1.1 g/dl, p=0.01). The rate of 30-day RC transfusion was similar in both groups (27.1 vs. 25.0% in the EPO and placebo groups, respectively; adjusted odds ratio 1.05, 95% CI: 0.42-2.64, p=0.92), and no differences were observed in the number of RC units per transfused patient (1 [1-3] vs. 2 [1-2] in the EPO and placebo groups, respectively, adjusted p=0.99). Rates of 30-day mortality, stroke, new-onset atrial fibrillation, acute kidney injury, and troponin peak were also similar between groups (p>0.20 for all). CONCLUSIONS EPO (+iron) administration failed to reduce RC transfusion rates or the per-patient number of transfusion units in anaemic patients undergoing TAVI.
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Effects of early parenteral iron combined erythropoietin in preterm infants: A randomized controlled trial.
Qiao, L, Tang, Q, Zhu, W, Zhang, H, Zhu, Y, Wang, H
Medicine. 2017;(9):e5795
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BACKGROUD The aim of the study was to evaluate the effect of early parenteral iron supplementation combined erythropoietin for prevention of anemia in preterm infants. METHODS In total, 96 preterm infants were randomly assigned to 3 groups: a control group receiving standard parenteral nutrition (group 1: n = 31), an iron-supplemented group (group 2: IS, n = 33), and an iron-supplemented combined erythropoietin group (group 3: IS+EPO, n = 32). The primary objective was to assess hemoglobin (Hb) levels. The secondary objectives included assessment of red blood cell counts (RBC), mean cell volume (MCV), serum iron, ferritin, percentages of reticulocyte (RET), total iron binding capacity (TIBC) and oxidative stress, which was assessed by measuring plasma levels of malondialdehyde and superoxide dismutase at baseline and at 2 weeks. The blood routine indices including Hb, RBC, MCV, and percentages of RET were measured at corrected age of 1 and 3 months. RESULTS At 2 weeks of life, the percentages of reticulocyte in group 2 and group 3 were significantly higher than those in group 1 (2.1±0.4, 2.5±0.3, and 1.7±0.3, respectively, P < 0.001, P<0.001), whereas TIBC were significantly lower than those in group 1 (36.7±4.6, 36.0±4.7, and 41.6 ± 5.2 respectively, P = 0.011, P = 0.006). There were no significant differences in RBC counts, the levels of hemoglobin, ferritin, malondialdehyde, and superoxide dismutase among the 3 groups at 2weeks of life. RBC, Hb, MCV, body weight, body length, and head circumference at a corrected age of 1 month did not differ among 3 groups. At corrected age of 3months, more infants in the control group had abnormal Hb and MCV levels (Hb levels: 114.3 ± 21.3, 123.7 ± 31.6, and 125.1 ± 21.2, P = 0.021, P = 0.034, respectively; MCV: 74.1 ± 3.5, 78.3 ± 4.7 and 79.1 ± 5.2, P = 0.017, P = 0.012, respectively), whereas cases of oral iron, cases of breastfeeding, RBC, body weight, body length, and head circumference were not different among 3 groups. CONCLUSION Early parenteral iron supplementation combined erythropoietin in preterm infants improved the percentages of reticulocyte, decreased total iron binding capacity, and improved the Hb and MCV levels at 3 months of age. Early parenteral iron supplementations with EPO were beneficial for the preterm infants.