Effect of Intravenous Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation (EFFECT-KTx): rationale and study protocol for a double-blind, randomised, placebo-controlled trial
BMJ open. 2023;13(3):e065423
INTRODUCTION Iron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs. METHODS AND ANALYSIS The Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin <100 µg/L or plasma ferritin 100-299 µg/L with transferrin saturation <20%. Patients are randomised to receive 10 mL of ferric carboxymaltose (50 mg Fe(3+)/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function. ETHICS AND DISSEMINATION The protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER NCT03769441.
Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery
Obesity surgery. 2022
PURPOSE Iron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery. MATERIALS AND METHODS Data were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia. RESULTS The analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed. CONCLUSIONS In patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated.
Iron Supplementation Effectively Ameliorates Anemia and Reduces the Need for Blood Transfusion in Patients Undergoing Colorectal Cancer Surgery: A Meta-Analysis
Nutrition and Cancer. 2022;74(7):2303-2312
OBJECTIVE Anemia is common and harmful in patients undergoing colorectal cancer (CRC) surgery. Blood transfusion (BT) is used to treat anemia, but results in a poor oncology prognosis. Iron supplementation may be effective in improving anemia and reducing the need for BT, however, the results remain controversial. This meta-analysis was conducted to evaluate the efficacy of iron supplementation in improving hemoglobin concentrations (Hb) and reducing the need for BT. METHODS Up to February 10, 2021, PubMed, Web of Science, Cochrane Library, Embase databases were searched for studies evaluating the effects of iron supplementation on CRC surgery patients. Meta-analysis was conduct using the random-effects model. RESULTS Seven trials with 879 participants in total were included in the meta-analysis. The pooled findings suggested that iron supplementation effectively increased Hb (MD 0.41; 95% CI: 0.12, 0.69, P = 0.006) and reduced the risk of BT (RR 0.60, 95% CI 0.45, 0.78, P = 0.0002) compared with the control group. In addition, subgroup analyses showed that these benefits were observed with both oral and intravenous iron supplementation. CONCLUSION Iron supplementation is effective in ameliorating anemia and reducing the need for BT in CRC surgery patients.
Iron supplementation following bariatric surgery: A systematic review of current strategies
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2021
Iron deficiency (ID) and iron deficiency anemia (IDA) are common following bariatric surgery; however, there are limited standardized treatment recommendations for their management. The purpose of this study was to review the current strategies for iron supplementation following bariatric surgery and assess their relative efficacy in managing ID and IDA. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched to January 2021. Primary outcomes of interest were prevention or improvement in ID or IDA with iron supplementation. Forty-nine studies with 12,880 patients were included. Most patients underwent Roux-en-Y gastric bypass (61.9%). Iron supplementation was most commonly administered orally for prevention of ID/IDA and was effective in 52% of studies. Both IV and oral iron were given for treatment of ID/IDA. Fifty percent (3/6) of the oral and 100% (3/3) of the IV supplementation strategies were effective at treating ID. Iron supplementation strategies employed following bariatric surgery are highly variable, and many do not provide sufficient iron to prevent the development of ID and IDA, potentially due to poor patient adherence. Further high-quality prospective trials, particularly comparing intravenous and oral iron, are warranted in order to determine the ideal dosage, route, and duration of iron supplementation.
Single-dose intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of post-operative anaemia in colorectal cancer patients: a randomised controlled trial
Blood transfusion = Trasfusione del sangue. 2021
BACKGROUND Recent clinical guidelines suggest that treatment of postoperative anaemia in colorectal cancer surgery with intravenous iron reduces transfusion requirements and improves outcomes. The study aimed at comparing two intravenous iron regimens in anaemic patients after colorectal cancer surgery. MATERIALS AND METHODS This was a single-centre, open-label, randomised, controlled trial in patients undergoing elective colorectal cancer surgery. Patients with moderate to severe anaemia (haemoglobin [Hb] <11 g/dL) after surgery were randomly assigned 1:1 to receive ferric carboxymaltose (FC; 1,000 mg, single dose) or iron sucrose (IS; 200 mg every 48 hours until covering the total iron deficit or discharge). Randomisation was stratified by Hb level: <10 g/dL (Group A) or ≥10-10.9 (Group B). The primary endpoint was the change in Hb concentration at postoperative day 30. Secondary endpoints included iron status parameters, transfusion requirements, complications, and length of hospital stay. RESULTS From September 2015 to May 2018, 104 patients were randomised (FC 50, IS 54). The median intravenous iron dose was 1,000 mg and 600 mg in the FC and IS groups, respectively. There were no between-group differences in mean change in Hb from postoperative day 1 to postoperative day 30 (FC: 2.5 g/dL, 95% CI: 2.1-2.9; IS: 2.4 g/dL, 95% CI: 2.0-2.8; p=0.52), in transfusion requirements or length of stay. The infection rate was lower in the FC group compared with the IS group (9.8% vs 37.2%, respectively). DISCUSSION The administration of approximately 500 mg of IS resulted in an increase in Hb at postoperative day 30 similar to that of 1,000 mg of FC, but it was associated with a higher infection rate. Future research will be needed to confirm the results, and to choose the best regime in terms of effectiveness and side effects to treat postoperative anaemia in colorectal cancer patients.
Physiological and Clinical Impact of Repeated Inhaled Oxygen Variation on Erythropoietin Levels in Patients After Surgery
Frontiers in physiology. 2021;12:744074
The "Normobaric Oxygen Paradox" (NOP) is a physiologic mechanism that induces an increase of endogenous erythropoietin (EPO) production by creating a state of relative hypoxia in subjects previously exposed to hyperoxia, followed by a rapid return to normoxia. Oxygen exposure duration and inspired oxygen fraction required to observe a significant increase in EPO or hemoglobin are not clearly defined. Consequently, we here study the effect of one model of relative hypoxia on EPO, reticulocytes and hemoglobin stimulation in patients after surgery. Patients were prospectively randomized in two groups. The O(2) group (n = 10) received 100% oxygen for 1 h per day for eight consecutive days, via a non-rebreathing mask. The control group (n = 12) received no oxygen variation. Serum EPO, hemoglobin and reticulocyte count were measured on admission and postoperatively on days seven and nine. Percentage EPO at day nine with respect to the baseline value was significantly elevated within the groups [O(2) group: 323.7 (SD ± 139.0); control group: 365.6 (SD± 162.0)] but not between them. No significant difference was found between the groups in terms of reticulocytes count and hemoglobin. Our NOP model showed no difference on EPO increase between the two groups. However, both groups expressed separately significant EPO elevation.
Intravenous iron supplementation after liver surgery: Impact on anemia, iron, and hepcidin levels-a randomized controlled trial
BACKGROUND Anemia is a recognized risk factor for perioperative related morbidity and mortality and is frequently reported in liver surgeries with an estimated incidence of 32%. We aim to assess the impact of intravenous iron administration in the immediate postoperative period on anemia and iron status as well as to determine the kinetics of hepcidin after liver surgery. METHODS The HepciFer trial, a randomized controlled trial, included 50 patients undergoing liver surgery. In accordance with the randomization process, patients received either ferric carboxymaltose (15 mg/kg, maximum 1 g) or placebo 4 hours after surgery. RESULTS The mean hemoglobin level, 7 days after surgery, did not differ significantly between the intervention and control group (11.1 ± 1.8 g/dL and 10.4 ± 1.6 g/dL, respectively) with a mean difference of +0.7 g/dL ([95% confidence interval, -0.3 to +1.7], P = .173). Within patients receiving intravenous iron supplementation, none presented biological signs of functional iron deficiency. Hepcidin levels remained significantly higher during the observation period in the intervention group. Inflammatory biomarkers, red blood cells transfusion rate and hospital duration of stay were similar between groups. CONCLUSION Intravenous ferric carboxymaltose administration did not result in a significant increase of hemoglobin levels 7 days after surgery. However, this study suggests that intravenous iron supplementation in the immediate postoperative settings prevents functional iron deficiency. Intravenous iron supplementation overcame the hepcidin-mediated blockade of iron absorption and should be considered as the preferred route of administration in the postoperative period.
Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial
Lancet (London, England). 2020
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.
Adults with preoperative anaemia before elective major open abdominal surgery (n= 487).
Intravenous iron: 1000 mg dose of ferric carboxymaltose (n= 244).
Placebo: 100 mL normal saline (n= 243).
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. There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group. There were no significant differences between the two groups for any of the prespecified safety endpoints.
Iron, Vitamin B(12), Folate and Copper Deficiency After Bariatric Surgery and the Impact on Anaemia: a Systematic Review
Obesity surgery. 2020
Bariatric surgery may increase the risk of iron, vitamin B(12), folate and copper deficiencies, which can cause anaemia. This review aims to critique the evidence on the prevalence of these nutritional deficiencies and the impact on anaemia in the first 12 months after surgery. PRISMA and MOOSE frameworks, the NHMRC evidence hierarchy and The Academy of Nutrition and Dietetics bias tool were used to systematically critique current literature. Seventeen studies reported on deficiency prevalence with the majority being of low quality. Important confounders to serum micronutrient levels were not adequately considered. Results on the prevalence of nutritional anaemias were also lacking. Further investigation into the prevalence of iron, vitamin B(12), folate and copper deficiency and its impact on anaemia in bariatric surgery is needed.
Epidemiology of parvovirus B19 and anemia among kidney transplant recipients: A meta-analysis
Urology annals. 2020;12(3):241-247
BACKGROUND Persistent anemia has been described in kidney transplant (KTx) recipients with parvovirus B19 virus infection. However, the epidemiology of parvovirus B19 and parvovirus B19-related anemia after KTx remains unclear. We conducted this systematic review (1) to investigate the incidence of parvovirus B19 infection after KTx and (2) to assess the incidence of parvovirus B19 among KTx patients with anemia. MATERIALS AND METHODS A systematic review was conducted in EMBASE, MEDLINE, and Cochrane databases from inception to March 2019 to identify studies that reported the incidence rate of parvovirus B19 infection and/or seroprevalence of parvovirus B19 in KTx recipients. Effect estimates from the individual studies were extracted and combined using random-effects, generic inverse variance method of DerSimonian and Laird. The protocol for this systematic review is registered with PROSPERO (no. CRD42019125716). RESULTS Nineteen observational studies with a total of 2108 KTx patients were enrolled. Overall, the pooled estimated seroprevalence of parvovirus B19 immunoglobulin G was 62.2% (95% confidence interval [CI]: 45.8%-76.1%). The pooled estimated incidence rate of positive parvovirus B19 DNA in the 1(st) year after KTx was 10.3% (95% CI: 5.5%-18.4%). After sensitivity analysis excluded a study that solely included KTx patients with anemia, the pooled estimated incidence rate of positive parvovirus B19 DNA after KTx was 7.6% (95% CI: 3.7%-15.0%). Among KTx with anemia, the pooled estimated incidence rate of positive parvovirus B19 DNA was 27.4% (95% CI: 16.6%-41.7%). Meta-regression analysis demonstrated no significant correlations between the year of study and the incidence rate of positive parvovirus B19 DNA (P = 0.33). Egger's regression asymmetry test was performed and demonstrated no publication bias in all analyses. CONCLUSION The overall estimated incidence of positive parvovirus B19 DNA after KTX is 10.3%. Among KTx with anemia, the incidence rate of positive parvovirus B19 DNA is 27.4%. The incidence of positive parvovirus B19 DNA does not seem to decrease overtime.