Interventions for treating iron deficiency anaemia in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials. SELECTION CRITERIA: Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision). AUTHORS' CONCLUSIONS: Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.

Parenteral versus oral iron therapy for adults and children with chronic kidney disease.

BACKGROUND: The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. This is an update of a review first published in 2012. OBJECTIVES: To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD, including participants on dialysis, with kidney transplants and CKD not requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in which IV and oral routes of iron administration were compared in adults and children with CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We included 39 studies (3852 participants), 11 of which were added in this update. A low risk of bias was attributed to 20 (51%) studies for sequence generation, 14 (36%) studies for allocation concealment, 22 (56%) studies for attrition bias and 20 (51%) for selective outcome reporting. All studies were at a high risk of performance bias. However, all studies were considered at low risk of detection bias because the primary outcome in all studies was laboratory-based and unlikely to be influenced by lack of blinding.There is insufficient evidence to suggest that IV iron compared with oral iron makes any difference to death (all causes) (11 studies, 1952 participants: RR 1.12, 95% CI 0.64, 1.94) (absolute effect: 33 participants per 1000 with IV iron versus 31 per 1000 with oral iron), the number of participants needing to start dialysis (4 studies, 743 participants: RR 0.81, 95% CI 0.41, 1.61) or the number needing blood transfusions (5 studies, 774 participants: RR 0.86, 95% CI 0.55, 1.34) (absolute effect: 87 per 1,000 with IV iron versus 101 per 1,000 with oral iron). These analyses were assessed as having low certainty evidence. It is uncertain whether IV iron compared with oral iron reduces cardiovascular death because the certainty of this evidence was very low (3 studies, 206 participants: RR 1.71, 95% CI 0.41 to 7.18). Quality of life was reported in five studies with four reporting no difference between treatment groups and one reporting improvement in participants treated with IV iron.IV iron compared with oral iron may increase the numbers of participants, who experience allergic reactions or hypotension (15 studies, 2607 participants: RR 3.56, 95% CI 1.88 to 6.74) (absolute harm: 24 per 1000 with IV iron versus 7 per 1000) but may reduce the number of participants with all gastrointestinal adverse effects (14 studies, 1986 participants: RR 0.47, 95% CI 0.33 to 0.66) (absolute benefit: 150 per 1000 with IV iron versus 319 per 1000). These analyses were assessed as having low certainty evidence.IV iron compared with oral iron may increase the number of participants who achieve target haemoglobin (13 studies, 2206 participants: RR 1.71, 95% CI 1.43 to 2.04) (absolute benefit: 542 participants per 1,000 with IV iron versus 317 per 1000 with oral iron), increased haemoglobin (31 studies, 3373 participants: MD 0.72 g/dL, 95% CI 0.39 to 1.05); ferritin (33 studies, 3389 participants: MD 224.84 µg/L, 95% CI 165.85 to 283.83) and transferrin saturation (27 studies, 3089 participants: MD 7.69%, 95% CI 5.10 to 10.28), and may reduce the dose required of erythropoietin-stimulating agents (ESAs) (11 studies, 522 participants: SMD -0.72, 95% CI -1.12 to -0.31) while making little or no difference to glomerular filtration rate (8 studies, 1052 participants: 0.83 mL/min, 95% CI -0.79 to 2.44). All analyses were assessed as having low certainty evidence. There were moderate to high degrees of heterogeneity in these analyses but in meta-regression, definite reasons for this could not be determined. AUTHORS' CONCLUSIONS: The included studies provide low certainty evidence that IV iron compared with oral iron increases haemoglobin, ferritin and transferrin levels in CKD participants, increases the number of participants who achieve target haemoglobin and reduces ESA requirements. However, there is insufficient evidence to determine whether IV iron compared with oral iron influences death (all causes), cardiovascular death and quality of life though most studies reported only short periods of follow-up. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes with longer follow-up periods are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects.

ASSOCIATION BETWEEN ORAL IRON SUPPLEMENTATION AND RETINAL OR SUBRETINAL HEMORRHAGE IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENT TRIALS.

PURPOSE: Because patients often take iron supplements without medical indication, and iron can accumulate in vascular endothelial cells, the authors evaluated the association of oral iron supplementation with retinal/subretinal hemorrhage in patients with neovascular age-related macular degeneration. METHODS: A post hoc secondary data analysis of comparison of age-related macular degeneration treatments trials was performed. Participants were interviewed for use of oral iron supplements. Trained readers evaluated retinal/subretinal hemorrhage in baseline fundus photographs. Adjusted odds ratios from multivariate logistic regression models assessed the association between iron use and baseline hemorrhage adjusted by age, sex, smoking, hypertension, anemia, and use of antiplatelet/anticoagulant drugs. RESULTS: Among 1,165 participants, baseline retinal/subretinal hemorrhage was present in the study eye in 71% of 181 iron users and in 61% of 984 participants without iron use (adjusted odds ratio = 1.47, P = 0.04), and the association was dose dependent (adjusted linear trend P = 0.048). Iron use was associated with hemorrhage in participants with hypertension (adjusted odds ratio = 1.87, P = 0.006) but not without hypertension. The association of iron use with hemorrhage remained significant among hypertensive participants without anemia (adjusted odds ratio = 1.85, P = 0.02). CONCLUSION: Among participants of comparison of age-related macular degeneration treatments trials, the use of oral iron supplements was associated with retinal/subretinal hemorrhage in a dose-response manner. Unindicated iron supplementation may be detrimental in patients with wet age-related macular degeneration.

Intravenous Iron for Treatment of Anemia in the 3 Perisurgical Phases: A Review and Analysis of the Current Literature.

Anemia is a common comorbidity throughout the entire hospital stay. Treatment options include intravenous (IV) iron, oral iron, erythropoietin, and red blood cell (RBC) transfusions. IV iron has gained in popularity with the implementation of patient blood management programs. A variety of studies have been performed to investigate the use of IV iron in preoperative, perioperative, and postoperative settings. An objective review on these studies has yet to be performed. The current narrative review provides an overview of trials investigating IV iron use in the preoperative, perioperative, and postoperative settings. We performed a literature research of English articles published between 1964 and March 2017 in Pubmed including Medline and The Cochrane Library. Only studies with a control group were included. The final review includes 20 randomized controlled trials (RCTs), 7 observational trials, and 5 retrospective studies. Measured outcomes included hemoglobin (Hb) levels, reticulocyte counts, and/or RBC concentrates. Meta-analyses of RCTs using IV iron administration before surgery led to an increase in Hb levels, a reduction of RBC use, and an improvement in patient outcome. Only a few studies investigated the use of IV iron in the perioperative setting. These studies recommended the use of perioperative IV iron in cases of severe anemia in orthopedic surgery but not in all types of surgery. Published RCTs in the postoperative setting have shown positive effects of IV iron on Hb levels, length of hospital stay, and transfusion requirements. Some studies demonstrated an increase of Hb of 0.5-1 g/dL over 4 weeks postoperatively, but the clinical relevance and effect of this increase on an improvement of patient's long-term outcomes are uncertain. To summarize, the evidence to use IV iron is strongest in the preoperative setting, while it remains an individual treatment decision to administer IV iron perioperatively or postoperatively.

Treating Anemia in the Preanesthesia Assessment Clinic: Results of a Retrospective Evaluation.

BACKGROUND: Perioperative anemia is challenging during hospital stay because anemia and red blood cell (RBC) transfusions are associated with an increased morbidity and mortality. With the implementation of patient blood management (PBM), a preanesthesia assessment clinic to screen and treat anemia before elective surgery was institutionalized at Muenster University Hospital, Germany. The main objective of this study was to evaluate the association between treating preoperative anemic patients with intravenous iron (IVI) and (primarily) presurgical hemoglobin levels and (secondarily) use of RBCs and mortality. METHODS: Between April 1, 2014, and July 4, 2016, patients scheduled for elective surgery with a risk for RBC transfusions >10% in 2013 were screened for preoperative anemia and, if indicated, treated with IVI. Patients' data, time span between visit in the anesthesia/PBM clinic and surgery, demographic data, type of surgery, the difference of hemoglobin levels between visit and surgery, RBC transfusion, infectious-related International Classification of Disease codes during hospital stay, and 1-year survival were determined retrospectively by screening electronic data files. In addition, patients were interviewed about adverse events, health-related events, and infections via telephone 30, 90, and 365 days after visiting the anesthesia/PBM clinic. RESULTS: A total of 1101 patients were seen in the anesthesia/PBM clinic between days -28 and -1 (median [Q1-Q3], -3 days [-1, -9 days]) before elective surgery. Approximately 29% of patients presented with anemia, 46.8% of these anemic patients were treated with ferric carboxymaltose (500-1000 mg).In the primary analysis, hemoglobin levels at median were associated with a reduction between the visit in the anesthesia/PBM clinic and the surgery in all nonanemic patients on beginning of medical treatment (nonanemic patients at median -2.8 g/dL [-4, -0.9 g/dL], while anemic patients without IVI presented with median differences of -0.8 g/dL [-2, 0 g/dL] and anemic patients with IVI of 0 g/dL [-1.0, 0.5 g/dL]). Hemoglobin levels raised best at substitution 22-28 days before surgery (0.95 g/dL [-0.35, 1.18 g/dL]). Due to the selection criteria, transfusion rates were high in the cohort. Overall, there was no association between IVI treatment and the use of RBC transfusions (odds ratio for use of RBCs in anemic patients, no IVI versus IVI: 1.14; 95% confidence interval, 0.72-1.82). Patients treated with or without IVI presented a comparable range of International Classification of Disease codes related to infections. Telephone interviews indicated similar adverse events, health-related events, and infections. Cox regression analysis showed an association between anemia and reduced survival, regardless of IVI. CONCLUSIONS: An anemia clinic within the preanesthesia assessment clinic is a feasible and effective approach to treat preoperative anemia. The IVI supplementation was safe but was associated with decreased RBC transfusions in gynecology/obstetric patients only. The conclusions from this retrospective analysis have to be tested in prospective, controlled trials.

Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).

BACKGROUND: Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES: The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS: We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based binders. Compared with calcium-based binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS: In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based binders may lead to diarrhoea.

Safety and efficacy of intravenous iron administration for uterine bleeding or postpartum anaemia: a narrative review.

The management of iron deficiency anaemia (IDA) consists of oral or intravenous administration of iron supplements. The aim of this narrative review is to summarise information regarding the treatment of IDA in women who have postpartum anaemia or uterine bleeding with intravenous (IV) or oral iron supplements. Fourteen randomised control studies comparing IV to oral iron treatment for IDA in 2913 women with uterine bleeding or postpartum haemorrhage are included. All reviewed studies suggest that IV iron administration is important in treating the IDA in such women and in improving their physical performance and quality of life. Comparisons among intravenous iron supplements show advantages of ferric carboxymaltose over others in time of reaching desired haemoglobin and ferritin values and in adverse reactions. Despite the limitation that the above evidence emerges from not systematically collected data, our review highlights that new forms of IV iron supplements seem safe and efficient in treating IDA.

[Iron, a "miralcle cure" for chronic cardiac insufficiency?] / Eisen, ein Wundermittel bei Herzinsuffizienz?

Anemia and chronic heart failure are frequent comorbidities in geriatric patients. In approximately one third of older adults the cause of the anemia is an iron, vitamin B12 and/or folate deficiency and in another third a chronic inflammatory process is present. In the case of iron deficiency a differentiation must be made between the absolute and functional forms. Although in functional iron deficiency ferritin, as a parameter of iron metabolism, is within the normal range or can even be higher, an iron-deficient erythropoiesis is present. In cardiac insufficiency a chronic inflammatory process is assumed. According to the recent guidelines of the Deutsche Gesellschaft für Kardiologie (DGK, German Cardiac Society) and European Society of Cardiology (ESC) a routine contol of the iron status should be performed and, if necessary, initiation of adequate supplementation is recommended.

Iron-induced hypophosphatemia: an emerging complication.

PURPOSE OF REVIEW: Iron-induced hypophosphatemia is a well documented side-effect but associated complications are largely neglected, because the results from single dosing studies suggest that transient decreases in plasma phosphate concentrations are asymptomatic and fully reversible. However, an increasing number of case reports and case series suggest that some patients develop severe and symptomatic hypophosphatemia. Long-term complications from hypophosphatemia include osteomalacia and bone fractures, which can result from repeated intravenous administration of certain high-dose iron preparations. RECENT FINDINGS: Results from clinical trials suggest that the highest risk for the development of hypophosphatemia is associated with ferric carboxymaltose, iron polymaltose, and saccharated iron oxide. Clinical studies show that renal phosphate wasting mediated by increased fibroblast growth factor 23 causes hypophosphatemia after iron therapy. Impaired renal function therefore protects from hypophosphatemia, whereas the highest incidences and most severe manifestations have been reported in patients in whom the underlying cause of iron deficiency cannot be corrected. SUMMARY: Diagnosis of iron-induced hypophosphatemia requires clinical suspicion. Treatment is guided by the severity of hypophosphatemia, and most patients will require oral or intravenous phosphate substitution. Future treatment options could involve therapeutic anti-FGF23 antibody (KRN23). Prevention and correction of vitamin D deficiency represents a supportive treatment option.

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

IMPORTANCE: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. OBJECTIVE: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. DESIGN, SETTING, AND PARTICIPANTS: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites. INTERVENTIONS: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). RESULTS: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05. CONCLUSIONS AND RELEVANCE: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02188784.

Effect of Low-Dose Ferrous Sulfate vs Iron Polysaccharide Complex on Hemoglobin Concentration in Young Children With Nutritional Iron-Deficiency Anemia: A Randomized Clinical Trial.

Importance: Iron-deficiency anemia (IDA) affects millions of persons worldwide, and is associated with impaired neurodevelopment in infants and children. Ferrous sulfate is the most commonly prescribed oral iron despite iron polysaccharide complex possibly being better tolerated. Objective: To compare the effect of ferrous sulfate with iron polysaccharide complex on hemoglobin concentration in infants and children with nutritional IDA. Design, Setting, and Participants: Double-blind, superiority randomized clinical trial of infants and children aged 9 to 48 months with nutritional IDA (assessed by history and laboratory criteria) that was conducted in an outpatient hematology clinic at a US tertiary care hospital from September 2013 through November 2015; 12-week follow-up ended in January 2016. Interventions: Three mg/kg of elemental iron once daily as either ferrous sulfate drops or iron polysaccharide complex drops for 12 weeks. Main Outcomes and Measures: Primary outcome was change in hemoglobin over 12 weeks. Secondary outcomes included complete resolution of IDA (defined as hemoglobin concentration >11 g/dL, mean corpuscular volume >70 fL, reticulocyte hemoglobin equivalent >25 pg, serum ferritin level >15 ng/mL, and total iron-binding capacity <425 µg/dL at the 12-week visit), changes in serum ferritin level and total iron-binding capacity, adverse effects. Results: Of 80 randomized infants and children (median age, 22 months; 55% male; 61% Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31 [78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group), a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P < .001) with ferrous sulfate (based on a linear mixed model). Proportion with a complete resolution of IDA was higher in the ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to 15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P < .001) with ferrous sulfate. Mean total iron-binding capacity decreased from 501 to 389 µg/dL (ferrous sulfate) vs 506 to 417 µg/dL (iron complex) (a greater difference of -50 µg/dL [95% CI, -86 to -14 µg/dL] with ferrous sulfate; P < .001). There were more reports of diarrhea in the iron complex group than in the ferrous sulfate group (58% vs 35%, respectively; P = .04). Conclusions and Relevance: Among infants and children aged 9 to 48 months with nutritional iron-deficiency anemia, ferrous sulfate compared with iron polysaccharide complex resulted in a greater increase in hemoglobin concentration at 12 weeks. Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia. Trial Registration: clinicaltrials.gov Identifier: NCT01904864.

Emerging drugs for the treatment of kidney disease-induced anemia.

INTRODUCTION: Anemia has been remained one of the most characteristic and visible manifestations of chronic renal failure. Correction of anemia requires two main treatment strategies: increased stimulation of erythropoiesis, and maintenance of an adequate iron supply to the bone marrow. AREAS COVERED: Erythropoiesis activating agents became a mainstay in the treatment of renal anemia for more than 25 years. Recently, there have been several attempts to introduce new drugs to stimulate erythropoiesis or affect the hepcidin-ferroportin pathway. Orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives. They not only increase hemoglobin, but also suppress hepcidin production and improve iron availability. Novel iron preparations, may also help to ameliorate anemia, with acceptable safety profile and other beneficial properties such a phosphate binding. EXPERT OPINION: One should be aware of potential risks and benefits of novel sophisticated therapies and their role in the management of renal anemia remain to be established. In particular HIF stabilizers needs to be proven safe, or even safer than ESAs, in large long-term safety studies testing hard end points, due its ubiquitous nature and the regulation of variety of biological processes potentially leading to unexpected side effects. Besides safety, cost-effectiveness appears the major issue in the modern world, including nephrology.

Heme iron polypeptide for the management of anaemia of chronic kidney disease.

WHAT IS KNOWN AND OBJECTIVE: Anaemia is a common clinical finding among patients with chronic kidney disease (CKD) and is associated with significant morbidity and healthcare costs. Iron deficiency is an important contributing factor, and adequate iron supplementation is essential to optimize the management of anaemia of CKD. Oral iron is convenient and inexpensive but is poorly absorbed and associated with gastrointestinal distress. Intravenous iron overcomes these limitations but is more expensive, requires additional clinical visits for administration and is associated with serious adverse events. Oral heme iron polypeptide (HIP) is a newer dosage form that has been reported to have higher bioavailability and fewer side effects when compared with non-heme iron in healthy subjects, but data in patients with CKD are limited. The purpose of this review is to evaluate the safety and effectiveness of HIP for the management of CKD. METHODS: Searches for PubMed (1947-2015) and International Pharmaceutical Abstracts (1970-2015) were conducted using the following terms: heme iron, heme iron polypeptide, oral iron, anaemia and chronic kidney disease. The bibliography of each relevant article was evaluated for additional studies. Articles were selected for review if they were published in the English language and were randomized controlled trials evaluating the bioavailability, tolerability or efficacy of oral HIP in human subjects with CKD. RESULTS AND DISCUSSION: This search yielded three clinical studies. The safety and efficacy of HIP was evaluated in a total of 161 subjects with anaemia and various stages of CKD. HIP was consistently associated with lower ferritin values when compared with traditional iron supplementation. With few exceptions, the effect of HIP on haemoglobin, haematocrit, transferrin saturation and recombinant human erythropoietin dose, and adverse effects appeared similar to intravenous and oral non-heme iron supplementation. The cost of HIP is substantially more than non-heme iron and comparable to intravenous iron. WHAT IS NEW AND CONCLUSION: Heme iron polypeptide does not appear to confer benefit over traditional iron supplementation among patients with anaemia of CKD and is more expensive.

Intravenous Iron Sucrose versus Oral Iron in the Treatment of Pregnancy with Iron Deficiency Anaemia: A Systematic Review.

BACKGROUND: Intravenous iron sucrose and oral iron therapy are the main therapies for iron deficiency anaemia (IDA), but there is still a debate regarding their efficacy and especially as to which one is the best choice during pregnancy. METHODS: A meta-analysis of randomised controlled trials comparing patients treated with intravenous iron sucrose (intravenous group) with those treated with oral iron (oral group) for IDA during pregnancy was performed. The primary outcomes of interest were mean maternal haemoglobin and serum ferritin levels at the end of treatment. Secondary outcomes were treatment-related adverse events and foetal birth weight. RESULTS: Six randomised controlled trials, involving a total of 576 women, were included in the present review. Significant increases in haemoglobin [mean difference (MD), 0.85; 95% confidence interval (CI), 0.31-1.39; p = 0.002] and ferritin levels (MD, 63.32; 95% CI, 39.46-87.18; p < 0.00001) were observed in the intravenous group. Compared with the oral group, there were fewer adverse events in the intravenous group (risk ratio, 0.50; 95% CI, 0.34-0.73; p = 0.0003). There was no significant difference in birth weight between the two groups. CONCLUSION: For pregnant women who could not tolerate the side effects of oral treatment or required a rapid replacement of iron stores, intravenous iron sucrose was associated with fewer adverse events and was more effective than regular oral iron therapy.

Efficacy and safety of intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients: a meta-analysis.

BACKGROUND: Studies on benefits of intravenous iron therapy among hemodialysis patients with functional iron deficiency anemia have shown conflicting results. We conducted a meta-analysis to assess the efficacy and safety of intravenous iron in this subset of patients. METHODS: We searched MEDLINE (through December 2012), the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for single-arm studies and randomized controlled trials (RCT) that examined the effect of intravenous iron for functional iron deficiency anemia in hemodialysis patients on anemia parameters and markers of oxidative stress and inflammation. Studies of absolute iron deficiency were excluded. Random-effect model meta-analyses were used to compute changes in outcomes of interest. RESULTS: We identified 34 studies (2,658 patients), representing 24 single-arm studies, and 10 parallel-arm RCT. In the analyses of the study arms, intravenous iron therapy resulted in a significant increase in hemoglobin, serum ferritin, transferrin saturation rate, serum iron, reticulocyte hemoglobin content as well as a significant decrease in the percentage of hypochromic erythrocytes and erythropoietin dose. There were significant increases in plasma malonyldialdehyde level and thiobarbituric acid-reactive substances, and a decrease in neutrophil respiratory burst. The analyses of the RCT revealed less robust net changes in these parameters, and there was no increased risk of adverse events including infections, cardiac events and mortality. CONCLUSIONS: Intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients improves anemia parameters but exerts some effects on markers of oxidative stress that are of unclear clinical significance. The long-term safety and efficacy of this treatment strategy requires further study.

Iron and infection in hemodialysis patients.

Intravenous iron is an important component of the treatment of anemia of end-stage renal disease (ESRD), but it is biologically plausible that iron could increase the risk of infection through impairment of neutrophil and T-cell function and promotion of microbial growth. Any such increase in risk would be particularly important because infection is a significant cause of mortality and morbidity in dialysis patients. The overall evidence favors an association between iron and infection in hemodialysis patients, but the optimal iron management strategy to minimize infection risk has yet to be identified. There is a need for further research on this topic, particularly in light of increased utilization of intravenous iron following implementation of the bundled ESRD reimbursement system.

Histologic findings following use of hydrophilic polymer with potassium ferrate for hemostasis.

Hydrophilic polymer with potassium salt is a hemostatic agent marketed for use by healthcare professionals and as an over-the-counter product available to healthcare consumers. In particular, dermatologic surgeons may use hydrophilic polymer for hemostasis in wounds left to heal by secondary intention. Foreign body reaction to hydrophilic polymer was recently reported. The microscopic findings in four additional patients treated with hydrophilic polymer are presented. The wounds of three patients were treated with hydrophilic polymer following a dermatologic surgical procedure while one patient used over-the-counter hydrophilic polymer on an abrasion. Three patients developed a foreign body reaction. Histopathologic examination revealed angulated fragments of deep purple material representing hydrophilic polymer admixed with round orange-red bodies and yellow-brown granules representing potassium ferrate. The components were found both free in the dermis and within multinucleated giant cells. Hydrophilic polymer must be differentiated from other materials observed in re-excision specimens, including ferric subsulfate, aluminum chloride and Gelfoam(®) (Pharmacia and Upjohn Co., New York, NY, USA).

Iron therapy in anaemic adults without chronic kidney disease.

BACKGROUND: Anaemia affects about a quarter of the world's population. An estimated 50% of anaemic people have anaemia due to iron deficiency. OBJECTIVES: To assess the safety and efficacy of iron therapies for the treatment of adults with anaemia who are not pregnant or lactating and do not have chronic kidney disease. SEARCH METHODS: We ran the search on 11 July 2013. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE (Ovid SP), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus (EBSCO Host), the Institute for Scientific Information Web of Science (ISI WOS) Scientific Citation Index (SCI)-EXPANDED (1970) and Conference Proceedings Citation Index (CPCI)-Science (1990) and Clinicaltrials.gov; we also screened reference lists. An updated search was run on 24 November 2014 but the results have not yet been incorporated into the review. SELECTION CRITERIA: Two review authors independently selected references for further assessment by going through all titles and abstracts. Further selection was based on review of full-text articles for selected references. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence interval (CI) for binary outcomes and the mean difference (MD) or the standardised mean difference (SMD) with 95% CI for continuous outcomes. We performed meta-analysis when possible, when I(2) was less than or equal to 80% using a fixed-effect or random-effects model, using Review Manager software. The range of point estimates for individual studies is presented when I(2) > 80%. MAIN RESULTS: We included in this systematic review 4745 participants who were randomly assigned in 21 trials. Trials were conducted in a wide variety of clinical settings. Most trials included participants with mild to moderate anaemia and excluded participants who were allergic to iron therapy. All trials were at high risk of bias for one or more domains. We compared both oral iron and parenteral iron versus inactive controls and compared different iron preparations.The comparison between oral iron and inactive control revealed no evidence of clinical benefit in terms of mortality (RR 1.05, 95% CI 0.68 to 1.61; four studies, N = 659; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged from 0.3 to 3.1 g/dL higher in the oral iron group than in the inactive control group. The proportion of participants who required blood transfusion was lower with oral iron than with inactive control (RR 0.74, 95% CI 0.55 to 0.99; three studies, N = 546; very low-quality evidence). Evidence was inadequate for determination of the effect of parenteral iron on mortality versus oral iron (RR 1.49, 95% CI 0.56 to 3.94; 10 studies, N = 2141; very low-quality evidence) or inactive control (RR 1.04, 95% CI 0.63 to 1.69; six studies, N = 1009; very low-quality evidence). Haemoglobin levels were higher with parenteral iron than with oral iron (MD -0.50 g/dL, 95% CI -0.73 to -0.27; six studies, N = 769; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged between 0.3 and 3.0 g/dL higher in the parenteral iron group than in the inactive control group. Differences in the proportion of participants requiring blood transfusion between parenteral iron and oral iron groups (RR 0.61, 95% CI 0.24 to 1.58; two studies, N = 371; very low-quality evidence) or between parenteral iron groups and inactive controls (RR 0.84, 95% CI 0.66 to 1.06; eight studies, N = 1315; very low-quality evidence) were imprecise. Average blood volume transfused was less in the parenteral iron group than in the oral iron group (MD -0.54 units, 95% CI -0.96 to -0.12; very low-quality evidence) based on one study involving 44 people. Differences between therapies in quality of life or in the proportion of participants with serious adverse events were imprecise (very low-quality evidence). No trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare. Adverse effects related to oral iron treatment included nausea, diarrhoea and constipation; most were mild.Comparisons of one iron preparation over another for mortality, haemoglobin or serious adverse events were imprecise. No information was available on quality of life. Thus, little evidence was found to support the use of one preparation or regimen over another.Subgroup analyses did not reveal consistent results; therefore we were unable to determine whether iron is useful in specific clinical situations, or whether iron therapy might be useful for people who are receiving erythropoietin. AUTHORS' CONCLUSIONS: • Very low-quality evidence suggests that oral iron might decrease the proportion of people who require blood transfusion, and no evidence indicates that it decreases mortality. Oral iron might be useful in adults who can tolerate the adverse events, which are usually mild.• Very low-quality evidence suggests that intravenous iron results in a modest increase in haemoglobin levels compared with oral iron or inactive control without clinical benefit.• No evidence can be found to show any advantage of one iron preparation or regimen over another.• Additional randomised controlled trials with low risk of bias and powered to measure clinically useful outcomes such as mortality, quality of life and blood transfusion requirements are needed.