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Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallel-group, open-label, randomised controlled phase 3 trial.
Vanobberghen, F, Lweno, O, Kuemmerle, A, Mwebi, KD, Asilia, P, Issa, A, Simon, B, Mswata, S, Schmidlin, S, Glass, TR, et al
The Lancet. Global health. 2021;(2):e189-e198
Abstract
BACKGROUND Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. METHODS This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 μg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin <100 g/L: 2000 mg in two doses at least 7 days apart). Oral iron treatment consisted of three dried ferrous sulphate tablets of 200 mg containing 60 mg of elementary iron and 5 mg of folic acid every morning. Oral treatment was to be taken for 3 months after haemoglobin normalisation. The primary outcome was haemoglobin normalisation (>115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-to-treat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. FINDINGS Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. INTERPRETATION Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting. FUNDING Vifor Pharma, R Geigy-Stiftung, Freiwillige Akademische Gesellschaft, and Swiss Tropical and Public Health Institute.
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Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.
Akizawa, T, Nangaku, M, Yonekawa, T, Okuda, N, Kawamatsu, S, Onoue, T, Endo, Y, Hara, K, Cobitz, AR
Clinical journal of the American Society of Nephrology : CJASN. 2020;(8):1155-1165
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BACKGROUND AND OBJECTIVES Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 μg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population. RESULTS Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa. CONCLUSIONS Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER 201754, Clinicaltrials.gov, NCT02969655.
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Beyond Hemoglobin: When and How to Work Up Possible Polycythemia Vera.
Shaw, G, Berg, R
Clinical medicine & research. 2020;(1):11-20
Abstract
BACKGROUND World Health Organization (WHO) 2017 diagnostic criteria for hemoglobin levels in polycythemia vera (PV) were lowered from 185 g/L to 165 g/L for men and from 165 g/L to 160 g/L for women, but these cutoffs were not designed for screening. OBJECTIVES The primary aim of this study was to assess the value of laboratory and clinical parameters in deciding whether to further pursue a diagnosis of PV. A secondary aim was to explore the diagnostic utility of bone marrow morphology. METHODS We evaluated clinical and laboratory parameters that may be useful when considering further diagnostic work-up, emphasizing PV vs. secondary erythrocytosis (SE). We classified 200 patients with JAK2 V617F testing using WHO criteria. RESULTS Patients with myeloproliferative neoplasms (MPN) were rarely under age 40 and uncommonly obese (BMI ≥ 30 kg/m2). Current smoking history favored SE, and these patients rarely had a platelet count ≥ 450 × 103/uL. Laboratory parameters suggesting greater PV likelihood were: RBC > 6.8 × 106 for men or > 5.9 × 106 for women; low erythropoietin; and low MCV or low ferritin. Bone marrow morphology (available in 111 cases) was generally more cellular in PV vs. SE and assessed disease progression. CONCLUSIONS Readily accessible clinical and laboratory data can assist in considering a PV workup, and a possible diagnostic algorithm is presented. These preliminary findings warrant larger studies to develop a more formal PV-risk scoring system with optimal cutoffs and weighting.
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Micronutrient-fortified infant cereal improves Hb status and reduces iron-deficiency anaemia in Indian infants: an effectiveness study.
Awasthi, S, Reddy, NU, Mitra, M, Singh, S, Ganguly, S, Jankovic, I, Grathwohl, D, Cercamondi, CI, Ghosh, A
The British journal of nutrition. 2020;(7):780-791
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Anaemia affects approximately 69 % of Indian children aged 6-12 months, with Fe deficiency (ID) being a common cause. The effectiveness of micronutrient-fortified infant cereal in improving Fe status and neurodevelopment was evaluated in non-anaemic and mildly anaemic Indian infants. An intervention group (IC) enrolled at age 6 months consumed 50 g/d of rice-based cereal providing 3·75 mg Fe/d as ferrous fumarate for 6 months (n 80) and was compared with a matched static cross-sectional control group (CG) without intervention enrolled at age 12 months (n 80). Mean Hb was higher in IC (118·1 (sd 10·2) g/l) v. CG (109·5 (sd 16·4) g/l) at age 12 months (adjusted mean difference: 9·7 g/l; 95 % CI 5·1, 14·3; P < 0·001), while geometric mean serum ferritin tended to be higher (27·0 (-1 sd 13·4, +1 sd 54·4) v. 20·3 (-1 sd 7·5, +1 sd 55·0) ng/ml); P = 0·085) and soluble transferrin receptor was lower (1·70 (-1 sd 1·19, +1 sd 2·43) v. 2·07 (-1 sd 1·29, +1 sd 3·33) mg/l; P = 0·014). Anaemia (23 v. 45 %; P = 0·007) and ID (17 v. 40 %; P = 0·003) were lower in IC v. CG. Bayley Scales of Infant and Toddler Development Third Edition scores for language (P = 0·003), motor development (P = 0·018), social-emotional (P = 0·004) and adaptive behaviour (P < 0·001), but not cognitive development (P = 0·980), were higher in IC v. CG. No significant difference in anthropometric Z-scores was observed between the groups. Consuming a micronutrient-fortified infant cereal daily for 6 months during complementary feeding promoted better Fe status while reducing the risk for anaemia and ID and was associated with superior neurodevelopmental scores.
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Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia.
Piga, A, Perrotta, S, Gamberini, MR, Voskaridou, E, Melpignano, A, Filosa, A, Caruso, V, Pietrangelo, A, Longo, F, Tartaglione, I, et al
Blood. 2019;(12):1279-1289
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β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
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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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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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Transcranial Doppler velocity among Jamaican children with sickle cell anaemia: determining the significance of haematological values and nutrition.
Rankine-Mullings, AE, Morrison-Levy, N, Soares, D, Aldred, K, King, L, Ali, S, Knight-Madden, JM, Wisdom-Phipps, M, Adams, RJ, Ware, RE, et al
British journal of haematology. 2018;(2):242-251
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This study investigated the association of nutritional and haematological variables with maximum time-averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (<170 cm/s), conditional (170-199 cm/s) and abnormal (≥200 cm/s) based on TAMV in distal internal carotid artery (dICA), middle cerebral artery (MCA), internal carotid bifurcation, anterior and posterior cerebral arteries. Of 358 children with sickle cell anaemia (SCA) examined, the mean age (±standard deviation) was 7·4 ± 2·7 years; 13·1% and 6·7% had conditional and abnormal velocities, respectively. Children with abnormal TCD velocities had higher prevalence of prior stroke (P = 0·006). Increased TAMV was associated with younger age (P = 0·001), lower weight (P = 0·001), height (P = 0·007) and oxygen saturation (P = 0·005). There was no association of TAMV with height-age or body mass index (BMI) z-scores. Adjusting for gender, BMI z-score, age, previous stroke and oxygen saturation, mean corpuscular volume (P = 0·005) and reticulocyte count (P = 0·013) were positively associated with TAMV, while haemoglobin concentration (P = 0·009) was negatively associated. There was good agreement [99%; weighted Kappa 0·98 (95% confidence interval 0·89-1), P = 0·0001] in TCD classification using data from five vessels versus two vessels (dICA and MCA). Haematological variables, rather than nutritional status, may be useful markers that identify high-risk children with SCA.
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Oral Iron Treatment Response and Predictors in Anaemic Adolescents and Adults with IBD: A Prospective Controlled Open-Label Trial.
Rampton, DS, Goodhand, JR, Joshi, NM, Karim, AB, Koodun, Y, Barakat, FM, Macken, L, Ward, DG, Iqbal, TH, Epstein, J, et al
Journal of Crohn's & colitis. 2017;(6):706-715
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BACKGROUND Because of previous concerns about the efficacy and safety of oral iron for treating iron deficiency anaemia in inflammatory bowel disease [IBD], particularly in young people, we compared the effects of ferrous sulphate on haemoglobin response, disease activity and psychometric scores in adolescents and adults with IBD. We also assessed the relation of baseline serum hepcidin to haemoglobin response. METHODS We undertook a prospective, open-label, 6-week non-inferiority trial of the effects of ferrous sulphate 200 mg twice daily on haemoglobin, iron status, hepcidin, disease activity (Harvey-Bradshaw Index, Simple Colitis Clinical Activity Index, C-reactive protein [CRP]), faecal calprotectin and psychometric scores in 45 adolescents [age 13-18 years] and 43 adults [>18 years]. RESULTS On intention-to-treat analysis, ferrous sulphate produced similar rises in haemoglobin in adolescents {before treatment 10.3 g/dl [0.18] (mean [SEM]), after 11.7 [0.23]: p < 0.0001} and adults (10.9 g/dl [0.14], 11.9 [0.19]: p < 0.0001); transferrin saturation, ferritin [in adolescents] and hepcidin [in adults] also increased significantly. On per-protocol univariate analysis, the haemoglobin response was inversely related to baseline haemoglobin, CRP and hepcidin. Oral iron did not alter disease activity; it improved Short IBDQ and Perceived Stress Questionnaire scores in adults. CONCLUSION Oral ferrous sulphate was no less effective or well-tolerated in adolescents than adults, and did not increase disease activity in this short-term study. The inverse relation between baseline CRP and hepcidin levels and the haemoglobin response suggests that CRP or hepcidin measurements could influence decisions on whether iron should be given orally or intravenously. [ClinTrials.gov registration number NCT01991314].
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Use of Reticulocyte Hemoglobin Content in the Assessment of Iron Deficiency in Children With Inflammatory Bowel Disease.
Syed, S, Kugathasan, S, Kumar, A, Prince, J, Schoen, BT, McCracken, C, Ziegler, TR, Suchdev, PS
Journal of pediatric gastroenterology and nutrition. 2017;(5):713-720
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BACKGROUND Iron deficiency and anemia affect up to 50% to 75% of patients with inflammatory bowel disease (IBD). Iron deficiency in IBD may be difficult to diagnose because of the effect of inflammation on iron status biomarkers. Thus, there is a need for better methods to accurately determine iron status in IBD. OBJECTIVE The aim of the study was to investigate the association of inflammation with hemoglobin content of reticulocytes (CHr) and the utility of CHr in comparison to standard iron biomarkers. METHODS We conducted a cross-sectional study of children with IBD. Iron biomarkers (CHr, ferritin, soluble transferrin receptor [sTfR], hepcidin, hemoglobin) were measured along with systemic biomarkers of inflammation (C-reactive protein, α1-acid glycoprotein]. Spearman correlations were used to evaluate the relation of inflammation and iron biomarkers. The criterion standard for iron deficiency was defined as inflammation-corrected ferritin <15 μg/L or sTfR >8.3 mg/L. Receiver operating characteristic curves were used to estimate the prognostic values of all iron biomarkers to identify patients with iron deficiency. RESULTS We analyzed data in 62 children ages 5 to 18 years. Sixty-nine percent of our subjects had Crohn disease and 31% had ulcerative colitis, of which 42% were girls and 53% African American. The prevalence of anemia was 32%, of iron deficiency was 52% using ferritin <15 μg/L or sTfR >8.3 mg/L, 39% using red blood cell distribution width of >14.5%, 26% using body iron stores of <0 mg/kg body weight, 25% using CHr of <28 pg, and 11% using mean corpuscular volume of <75 fL/cell. The prevalence of elevated CRP or AGP was 48%. After correcting ferritin and sTfR levels for inflammation, the prevalence of iron deficiency was 68%. CHr was correlated with C-reactive protein (rs -0.44, P < 0.001) and α1-acid glycoprotein (rs -0.37, P < 0.05). The optimal prognostic value for inflammation-adjusted CHr to predict iron deficiency was 34 pg (area under the receiver operating characteristic of 0.70), with 88% sensitivity and 30% specificity. CONCLUSIONS Iron deficiency and anemia are common in this pediatric IBD cohort. All explored iron biomarkers, including CHr, were affected by inflammation and should be adjusted. A single iron biomarker is unlikely to best predict iron deficiency in pediatric IBD. Iron intervention studies are needed to examine the response of iron biomarkers to iron supplementation in the setting of inflammation.
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Changes in body mass index and hemoglobin concentration in breastfeeding women living with HIV with a CD4 count over 350: Results from 4 African countries (The ANRS 12174 trial).
Somé, EN, Engebretsen, IMS, Nagot, N, Meda, NY, Vallo, R, Kankasa, C, Tumwine, JK, Singata, M, Hofmeyr, JG, Van de Perre, P, et al
PloS one. 2017;(5):e0177259
Abstract
INTRODUCTION Breastfeeding is recommended for infants born to HIV-infected women in low-income settings. Both breastfeeding and HIV-infection are energy demanding. Our objective was to explore how exclusive and predominant breastfeeding changes body mass index (BMI) among breastfeeding HIV1-positive women participating in the ANRS12174 trial (clinical trial no NCT0064026). METHODS HIV-positive women (n = 1 267) with CD4 count >350, intending to breastfeed HIV-negative infants were enrolled from Burkina Faso, South Africa, Uganda and Zambia and counselled on breastfeeding. N = 1 216 were included in the analysis. The trial compared Lamivudine and Lopinavir/Ritonavir as a peri-exposure prophylaxis. We ran a linear mixed-effect model with BMI as the dependent variable and exclusive or predominant breastfeeding duration as the key explanatory variable. RESULTS Any breastfeeding or exclusive/predominant) breastfeeding was initiated by 99.6% and 98.6% of the mothers respectively in the first week after birth. The median (interquartile range: IQR) duration of the group that did any breastfeeding or the group that did exclusive /predominant breastfeeding were 9.5 (7.5; 10.6) and 5.8 (5.6; 5.9)) months, respectively. The median (IQR) age, BMI, CD4 count, and HIV viral load at baseline (day 7) were 27 (23.3; 31) years, 23.7 (21.3; 27.0) kg/m2, 530 (432.5; 668.5) cells/μl and 0.1 (0.8; 13.7)1000 copies/mL, respectively. No major change in mean BMI was seen in this cohort over a 50-week period during lactation. The mean change between 26 and 50 weeks after birth was 0.7 kg/m2. Baseline mean BMI (measured on day 7 postpartum) and CD4 count were positively associated with maternal BMI change, with a mean increase of 1.0 kg/m2 (0.9; 1.0) per each additional baseline-BMI kilogram and 0.3 kg/m2 (0.2; 0.5) for each additional CD4 cell/μl, respectively. CONCLUSION Breastfeeding was not negatively correlated with the BMI of HIV-1 infected Sub-Saharan African mothers. However, a higher baseline BMI and a CD4 count >500 cells/μl were associated with maternal BMI during the exclusive/ predominant breastfeeding period. Considering the benefits of breast milk for the infants and the recurrent results from different studies that breastfeeding is not harmful to the HIV-1-infected mothers, this study also supports the WHO 2016 guidelines on infant feeding that mothers living with HIV should breastfeed where formula is not safe for at least 12 months and up to 24 months, given that the right treatment or prophylaxis for the infection is administered. These findings and conclusions cannot be extrapolated to women who are immune-compromised or have AIDS.