Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.

Introduction: The newest intravenous (IV) iron products show an improved safety profile over predecessors, allowing for the rapid administration of relatively high doses. Ferric derisomaltose (FDI; also known as iron isomaltoside), ferric carboxymaltose (FCM), and ferumoxytol (FER), are successful treatments for iron deficiency (Europe; FDI and FCM) and iron deficiency anemia (US; FDI, FCM, and FER).Areas covered: This review focusses on the chemistry and structure of FDI, FCM, and FER, and on three key aspects of IV iron safety: (1) hypersensitivity; (2) hypophosphatemia and sequelae; (3) cardiovascular safety.Expert opinion: Although the safety of modern IV iron has improved, immediate infusion reactions and the development of hypophosphatemia must be appreciated and recognized by those who prescribe and administer IV iron. Immediate infusion reactions can occur with any IV iron and are usually mild; severe reactions - particularly anaphylaxis - are extremely rare. The recognition and appropriate management of infusion reactions is an important consideration to the successful administration of IV iron. Severe, persistent, hypophosphatemia is a specific side effect of FCM. No cardiovascular safety signal has been identified for IV iron. Ongoing trials in heart failure will provide additional long-term efficacy and safety data.

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.

Improving the safety of intravenous iron treatments for patients with chronic kidney disease.

Introduction: Iron-deficiency anemia in chronic kidney disease (CKD) is common and has prognostic, financial, and quality of life implications. Intravenous (IV) iron is a key intervention for optimal management, however, ongoing safety concerns exist. Area covered: The potential side effects associated with IV iron use are addressed as we review the most recent studies. Hypersensitivity reactions and true anaphylaxis are indeed rare with a greater understanding of the nature of labile iron and 'Fishbane' reactions. Hypophosphatemia appears commoner with certain IV iron preparations, however its significance in CKD requires exploration. The long-standing questions regarding oxidative stress and the potential susceptibility to infections and worsening cardiovascular morbidity are discussed. Iron overload secondary to repeat IV iron infusions is plausible, however, a number of guidelines limit and strictly guide prescription. Expert opinion: The past decade has improved our understanding of IV iron administration safety in patients with CKD. Third generation IV iron compounds have minimized hypersensitivity reactions while allowing high doses to be administered safely and rapidly in non-dialysis-dependent CKD patients. However, differences in safety profiles such as hypophosphatemia require further study and therapy should be tailored to the individual. Clinicians should feel confident in using IV iron therapy.

The Influence of Antenatal Oral Iron and Folic Acid Side Effects on Supplementation Duration in Low-Resource Rural Kenya: A Cross-Sectional Study.

BACKGROUND: Undesirable effects of a daily regimen of iron and folic acid ingested jointly (iron-folate) are potential disincentives to optimal antenatal supplementation. We intended to profile antenatal iron-folate side effects and elucidate their influence on supplementation duration in low-resource rural Kenya. METHODS: This was a cross-sectional descriptive study of randomly selected postnatal mothers of under-five-year-old children. Using a modified WHO Safe Motherhood Assessment standard questionnaire, they recalled the total number of days of antenatal iron-folate intake and the attendant supplement-attributed undesirable experiences. The analyses considered only participants who ingested the supplements in their immediate last pregnancies (n = 277). RESULTS: About half of the study participants reported at least a side effect and a mean of 2.4 (SD 1.5) effects per person in the entire pregnancy period. Most common reported effects were chest pains (31.8%), constipation (28.5%), severe stomach pains (11.6%), and diarrhoea (11.6%). Mothers who reported at least a side effect ingested the supplements for ten days less compared to those who did not experience any effect (p = 0.03); and a greater proportion of the former were primigravida (p = 0.02) and used combined form of iron and folic acid (p = 0.003). In a multivariate analysis, significant correlations with supplementation compliance (ingestion for 90+ days) were found only for nausea and severe stomach pain experiences (r = -0.1, p = 0.04; r = 0.2, p = 0.01, resp.). CONCLUSIONS: The commonness of undesirable experiences attributed to daily ingestion of 60 mg iron and 0.4 mg folic acid and their deterrence to longer supplementation durations suggest the need for considering a weekly intermittent regimen for some antenatal women in such set-ups. Our study demonstrated that potentially, more counselling on nausea as a side effect might be critical in advancing iron-folate supplementation compliance.

Reported Severe Hypersensitivity Reactions after Intravenous Iron Administration in the European Economic Area (EEA) Before and After Implementation of Risk Minimization Measures.

INTRODUCTION: Severe hypersensitivity reactions (HSRs) such as anaphylaxis are of great clinical concern because of their life-threatening potential. The adverse events attributable to intravenous iron products include HSRs. An investigation by the European Medicines Agency presented in late 2013 resulted in the implementation of risk minimization measures (RMMs). OBJECTIVE: This study evaluated the number of severe HSRs reported for intravenous iron substances related to exposure for the 4-year periods before and after this implementation. METHODS: This was a retrospective pharmacoepidemiologic study with a case-population design. We obtained information from the safety surveillance database EudraVigilance on spontaneously reported severe HSRs using the Medical Dictionary for Regulatory Activities preferred terms "anaphylactic reaction/shock" and "anaphylactoid reaction/shock". Exposure was estimated using IQVIA MIDAS sales data in European economic area countries. RESULTS: Reporting rates for individual products were heterogenous, and the implementation of RMMs appeared to have no clear impact. Reporting rates remained low for the full study period for iron sucrose (0.03-0.20) and ferric gluconate (0.02-0.14) and were higher at the beginning and lower at the end of the study period for ferric carboxymaltose (1.47-0.18). No clear trend was detected for iron dextran (range 0.22-2.80) and iron (III) isomaltoside 1000 (range 0-7.94). CONCLUSIONS: Future research is needed to investigate whether the wide variability in reporting rates for severe HSRs associated with these intravenous iron products are due to potential differences in the safety profiles of these substances.

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.

Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial.

BACKGROUND: The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. METHODS: The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. RESULTS: The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. CONCLUSION: This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.

Assessment of adherence to iron supplementation among pregnant women in the Yaounde gynaeco-obstetric and paediatric hospital.

INTRODUCTION: Anemia is a global problem affecting 41.8% of pregnant women. Iron deficiency is the leading cause during pregnancy. Its prevalence among Cameroonian pregnant women was estimated at 50.9% in 2004. Few studies have evaluated women's adherence to iron supplementation prescribed during pregnancy. We carried this study in order to evaluate the rate of adherence to iron supplementation and its determinants during pregnancy. METHODS: The study was cross-sectional descriptive, on postpartum women at the Gynaeco-Obstetric and Pediatric Hospital of Yaoundé during three months. Adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). The total score was classified as low, moderate and high adherence. RESULTS: For a total of 304 recruited women, 16.4% were highly compliant, 27.6% moderately compliant, while 56% were low compliant with iron supplementation during pregnancy. The reasons for non-adherence were side effects (19.7%), forgetting (70.1%) and inaccessibility of iron supplements (20.1%). Up to 85 (or 28%) women found it boring to take medication daily. Women with no side effects were about thrice most likely to adhere to the iron supplementation than those with side effects: OR = 3.73 [2.43-5.71]; P = 0.04. Women aged 25 years and above were more likely to be non-compliant to iron supplementation than those youngers: OR = 0.40 [0.31-0.88]; P = 0.02. CONCLUSION: To improve adherence to antenatal iron supplementation, it is important to increase communication for behavior change and counseling before or during antenatal care. Forgetting being the main reason for non-adherence, women should keep their iron in a place of easy access.

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.

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.

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.

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.

[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.

The safety of available treatment options for iron-deficiency anemia.

INTRODUCTION: Iron deficiency (ID), with or without anemia, is highly prevalent worldwide and has clinical consequences. The prevention and treatment of ID is a major public health goal. Accurate diagnosis, selection of the appropriate iron replacement therapy and addressing the underlying cause, remain as the main challenges in ID management. AREAS COVERED: This review aims to provide a narrative review of current available evidence on iron supplementation options regularly used to treat ID, including oral and intravenous (IV) iron formulations, with emphasis on safety issues. Analyzed safety concerns include gastrointestinal side effects (oral iron) and risks of hypotension, anaphylaxis, infection, hypophosphatemia, oxidative stress and mortality (IV iron). EXPERT OPINION: Low-to-moderate doses of oral iron supplementation remains as first line therapy for uncomplicated ID, but it has been scarcely discussed in the setting of inflammation. Confirmatory studies on the efficacy of newer oral iron formulations in this setting are needed. Compared with oral iron, short-term IV iron administration is more efficacious in ID correction, without significant safety concerns. However, long-term safety of IV iron maintenance therapy, head to head comparisons of IV iron preparations, pharmacological modulation of hepcidin and HIF, and extra-erythropoietic effects of iron are among the important areas of research.

Iatrogenic iron overload and its potential consequences in patients on hemodialysis.

Iron overload was considered rare in hemodialysis patients until recently, but its clinical frequency is now increasingly recognized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Magnetic resonance imaging (MRI) is now the gold standard method for estimating and monitoring LIC. Studies of LIC in hemodialysis patients by magnetic susceptometry thirteen years ago and recently by quantitative MRI have demonstrated a relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Moreover, three recent long-term observational studies suggested that excessive IV iron doses might be associated with an increased risk of cardiovascular events and death in hemodialysis patients. It has been hypothesized that iatrogenic iron overload in the era of erythropoiesis-stimulating agents might silently increase complications in dialysis patients without creating obvious, clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It has been postulated that the main pathophysiological pathway leading to these events might involve the pleiotropic master hormone hepcidin, which regulates iron metabolism, leading to activation of macrophages in atherosclerotic plaques and then to clinical cardiovascular events. Thus, the potential iron overload toxicity linked to chronic administration of IV iron therapy is now becoming one of the most controversial topics in the management of anemia in hemodialysis patients.