A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia.

Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open­label, comparative, multi­center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1­5. Both non­inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.

Comparative Short-term Safety of Sodium Ferric Gluconate Versus Iron Sucrose in Hemodialysis Patients.

BACKGROUND: Despite different pharmacologic properties, little is known about the comparative safety of sodium ferric gluconate versus iron sucrose in hemodialysis patients. STUDY DESIGN: Retrospective cohort study using the clinical database of a large dialysis provider (2004-2005) merged with administrative data from the US Renal Data System. SETTING & PARTICIPANTS: 66,207 patients with Medicare coverage who received center-based hemodialysis. PREDICTORS: Iron formulation use assessed during repeated 1-month exposure periods (n=278,357). OUTCOMES: All-cause mortality, infection-related hospitalizations and mortality, and cardiovascular-related hospitalizations and mortality occurring during a 3-month follow-up period. MEASUREMENTS: For all outcomes, we estimated 90-day risk differences between the formulations using propensity score weighting of Kaplan-Meier functions, which controlled for a wide range of demographic, clinical, and laboratory variables. Risk differences were also estimated within various clinically important subgroups. RESULTS: Ferric gluconate was administered in 11.4%; iron sucrose, in 48.9%; and no iron in 39.7% of the periods. Risks for most study outcomes did not differ between ferric gluconate and iron sucrose; however, among patients with a hemodialysis catheter, use of ferric gluconate was associated with a slightly decreased risk for both infection-related death (risk difference, -0.3%; 95% CI, -0.5% to 0.0%) and infection-related hospitalization (risk difference, -1.5%; 95% CI, -2.3% to -0.6%). Bolus dosing was associated with an increase in infection-related events among both ferric gluconate and iron sucrose users. LIMITATIONS: Residual confounding and outcome measurement error. CONCLUSIONS: Overall, the 2 iron formulations studied exhibited similar safety profiles; however, ferric gluconate was associated with a slightly decreased risk for infection-related outcomes compared to iron sucrose among patients with a hemodialysis catheter. These associations should be explored further using other data or study designs.

AMD-like retinopathy associated with intravenous iron.

Iron accumulation in the retina is associated with the development of age-related macular degeneration (AMD). IV iron is a common method to treat iron deficiency anemia in adults, and its retinal manifestations have not hitherto been identified. To assess whether IV iron formulations can be retina-toxic, we generated a mouse model for iron-induced retinal damage. Male C57BL/6J mice were randomized into groups receiving IV iron-sucrose (+Fe) or 30% sucrose (-Fe). Iron levels in neurosensory retina (NSR), retinal pigment epithelium (RPE), and choroid were assessed using immunofluorescence, quantitative PCR, and the Perls' iron stain. Iron levels were most increased in the RPE and choroid while levels in the NSR did not differ significantly in +Fe mice compared to controls. Eyes from +Fe mice shared histological features with AMD, including Bruch's membrane (BrM) thickening with complement C3 deposition, as well as RPE hypertrophy and vacuolization. This focal degeneration correlated with areas of high choroidal iron levels. Ultrastructural analysis provided further detail of the RPE/photoreceptor outer segment vacuolization and Bruch's membrane thickening. Findings were correlated with a clinical case of a 43-year-old patient who developed numerous retinal drusen, the hallmark of AMD, within 11 months of IV iron therapy. Our results suggest that IV iron therapy may have the potential to induce or exacerbate a form of retinal degeneration. This retinal degeneration shares features with AMD, indicating the need for further study of AMD risk in patients receiving IV iron treatment.

Bullous Skin Lesions in a Patient with End-Stage Renal Disease and Hepatitis C.

Bullous lesions in patients with end-stage renal disease are uncommon and can pose diagnostic and therapeutic challenges. We present a female patient with end-stage renal disease, bullous skin lesions affecting mainly sun-exposed areas, and high ferritin levels. She also had hepatitis C. Her serum porphyrin panel was suggestive of porphyria cutanea tarda. Skin biopsy excluded inflammatory pathologies. Phlebotomy during each hemodialysis, continuation of darbepoetin, and avoidance of any further doses of intravenous iron, with close monitoring of hemoglobin, resulted in a gradual drop in ferritin level and improvement of the skin lesions.

A randomized trial of intravenous and oral iron in chronic kidney disease.

Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m(2), intravenous -4.0 ml/min per 1.73 m(2), between-group difference -0.35 ml/min per 1.73 m(2); 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56-4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24-3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases.

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.

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products.

IMPORTANCE: All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. OBJECTIVE: To compare the risk of anaphylaxis among marketed IV iron products. DESIGN, SETTING, AND PARTICIPANTS: Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. EXPOSURES: Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. MAIN OUTCOMES AND MEASURES: Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. RESULTS: A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4). CONCLUSIONS AND RELEVANCE: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

[Bone and Nutrition. The relationship between iron and phosphate metabolism].

Fibroblast growth factor 23 (FGF23) is an essential hormone for phosphate metabolism. It has been shown that intravenous administration of some iron formulations including saccharated ferric oxide induces hypophosphatemic osteomalacia with high FGF23 levels. On the other hand, iron deficiency promotes FGF23 and induces hypophosphatemia in patients with autosomal dominant hypophosphatemic rickets (ADHR). While iron and phosphate metabolism is connected, the detailed mechanism of this connection remains to be clarified.

A Phase III, randomized, open-label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy.

Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is used as first-line treatment, many patients are unresponsive to or cannot take oral iron. This Phase III, open-label, non-inferiority study compared the efficacy and safety of ferumoxytol, a rapid, injectable intravenous (IV) iron product with low immunological reactivity and minimal detectable free iron, with IV iron sucrose in adults with IDA of any cause. Patients (N = 605) were randomized 2:1 to receive ferumoxytol (n = 406, two doses of 510 mg 5 ± 3 days apart) or iron sucrose (n = 199, five doses of 200 mg on five nonconsecutive days over 14 days) and followed for 5 weeks. Ferumoxytol demonstrated noninferiority to iron sucrose at the primary endpoint, the proportion of patients achieving a hemoglobin increase of ≥2 g dL(-1) at any time from Baseline to Week 5 (ferumoxytol, 84.0% [n = 406] vs. iron sucrose, 81.4% [n = 199]), with a noninferiority margin of 15%. Ferumoxytol was superior to iron sucrose (2.7 g dL(-1) vs. 2.4 g dL(-1) ) in the mean change in hemoglobin from Baseline to Week 5 (the alternative preplanned primary endpoint) with P = 0.0124. Transferrin saturation, quality-of-life measures, and safety outcomes were similar between the two treatment groups. Overall, ferumoxytol demonstrated comparable safety and efficacy to iron sucrose, suggesting that ferumoxytol may be a useful treatment option for patients with IDA in whom oral iron was unsatisfactory or could not be used.

Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial.

AIM: Iron deficiency is a leading cause of anemia in pregnancy. The present study aimed to compare the efficacy of oral and intravenous iron therapy in improving iron deficiency anemia in pregnancy and restoring iron stores, compare the obstetric outcome in the two groups and evaluate the safety of intravenous iron sucrose. MATERIAL AND METHODS: This was a prospective study, where 100 anemic antenatal women with hemoglobin 7-9 g/dL, mean corpuscular volume <85 fL and serum ferritin <15 ng/mL, were randomized into two groups. In group A (n=50), the women received 200 mg tablets of ferrous sulphate, each containing 60 mg elemental iron, three times a day for 4 weeks. In group B (n=50), iron sucrose was given in divided doses of 200 mg each on alternate days by slow intravenous infusion. Primary outcome measure was treatment efficacy, assessed by measurement of hemoglobin, red blood cell indices and reticulocytes on days 7, 14, 21, and 30 and at delivery, and of ferritin on day 30 and at delivery. Any side-effects of treatment and the neonatal outcome were studied as secondary outcome measures. RESULTS: There was a statistically significant difference in increase of hemoglobin levels (3.1g/dL in group A vs 5.1 g/dL in group B; P=0.002) and ferritin levels between the two groups on day 30 (P=0.005). The adverse effects from iron treatment were mild but more prominent in group A. Neonatal outcome was comparable in the two groups. CONCLUSION: Intravenous administration of iron sucrose is a safe treatment for correction of anemia in pregnancy, without serious side-effects.

Iatrogenic osteomalacia: report of two cases.

UNLABELLED: CASE 1: An 80-year-old man presented at our hospital with pain in both knees.He had received continuous intravenous administration of saccharated ferric oxide (SFO) over a period of five years following a diagnosis of iron-deficiency anemia.Blood tests revealed hypophosphatemia (1.4 mg/dl) and high circulating levels of fibroblast growth factor 23 (FGF23) at 248.8 mg/dl.These findings led to the diagnosis of FGF23-related osteomalacia due to SFO administration.Accordingly, the treatment plan was first to discontinue SFO, which led to a decrease in pain and normalization of phosphorus and FGF23 after 1 month.CASE 2: A 63-year-old woman presented at our hospital with leg pain.She had undergone total gastrectomy for gastric cancer at 36 years of age.Blood tests revealed hypocalcemia (8.3 mg/dl) and hypophosphatemia (2.2 mg/dl), and 25(OH)D at no more than 5 pg/ml.Bone X-rays showed significantly diminished bone shadowing.These findings led to a diagnosis of vitamin D-deficient osteomalacia due to impaired absorption following total gastrectomy.For therapy, she was treated with 1 µg/day oral alfacalcidol.Two months after initiating treatment, the pain improved. CONCLUSION: When a patient is diagnosed with unexplained pain, it is important to pay attention to the possibility of an iatrogenic etiology.

[Updates on rickets and osteomalacia: FGF23-mediated hypophosphatemic rickets/osteomalacia].

Some of the hypophosphatemic rickets/osteomalacia are caused by the increased bioactivity of FGF23, and classified into FGF23-mediated hypophosphatemic rickets/osteomalacia. This group includes various disorders such as X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia, tumor-induced osteomalacia, and rickets/osteomalacia caused by the administration of iron polymaltose or saccharated ferric oxide. Measurement of serum levels of FGF23 is useful for diagnosis of these conditions. In the adult patients with FGF23-mediated hypophosphatemic rickets/osteomalacia, mineralizing enthesoopathy is an often observed complication.

[Importance of the different i.v. iron generations for everyday medical practice]. / Bedeutung der verschiedenen i.v.-Eisengenerationen für den medizinischen Alltag.

BACKGROUND: Iron deficiency and anaemia occur in particular in women or as comorbid conditions to a varietyof chronic diseases. Besides oral preparations, parenteral iron therapies are also available for the treatment of iron deficiency or anaemia. In the light of the growing importance and increasing number of parenteral iron preparations, theirpharmacology and application as well as the chronology of their approvals and thecharacteristicsof the various preparations are presented herefor comparison. METHOD: Review. RESULTS: To date, there are three different generations of parenteral iron preparations, which differ in terms of stability, safety and dosage. In particular, the active substances of the third generation, ferric carboxymaltose, iron isomaltoside and ferumoxytol are characterised by high complex stability and comparable safety, also allowing rapid application of high doses of iron. CONCLUSIONS: High molecular weight iron dextran, as a representative of 1st generation iron preparations, should no longer be used if possible, as more recent i.v. iron preparations are available with considerably lower risk of serious anaphylactic reactions. Ferrous gluconate and iron sucrose, as representatives of the 2nd generation, are very efficient preparations, but they require frequent visits to the clinic or the doctor, as they may only be administered in low doses because of labile iron complexes. The three 3rd generation parenteral iron formulations have advantages in handling in everyday practice, since they offer comparably good safety profiles, high complex stability and thus the possibility of rapid application of high doses of iron up to the total cumulative dose. Furthermore, test doses are not required with these preparations, which also simplifies their use.

Comparative rates of adverse events with different formulations of intravenous iron.

Oral iron replacement is the standard therapy in iron-deficiency anemia (IDA). However, 59% of patients have gastrointestinal toxicity. With impaired iron uptake from the gastrointestinal tract (in anemia of chronic disease (ACD) or after bariatric surgery), suboptimal responsiveness to exogenous erythropoietin (in chronic renal failure), in patients with cancer receiving chemotherapy, or when oral iron is poorly tolerated, IV iron therapy is the preferred mode of repletion. Although effective in increasing hemoglobin, the relative safety of the available IV iron preparations is not well documented. We examined the comparative safety of IV iron formulations used at hospitals associated with our institution. Among 619 unique patients who received IV iron over a 2-year period, we found 32 adverse events (AEs), ranging from urticaria to chest pain. There were no serious AEs or anaphylactic-type reactions. In a multivariate model, there was no difference in AE rates between low-molecular-weight iron dextran (LMWD) and ferric gluconate; however, iron sucrose had significantly higher odds ratio of AEs (OR = 5.7; 95% CI = 1.6­21.3). Our data suggest that AE rates with IV iron are acceptable. More widespread use of LMWD, in particular, which can be given safely as a total dose infusion (TDI), should be considered.

Safety and efficacy of high-dose intravenous iron carboxymaltose vs. iron sucrose for treatment of postpartum anemia.

OBJECTIVE: The purpose of this study is to compare the safety and efficacy of intravenous (IV) high-dose iron carboxymaltose (ICM) with iron sucrose (IS) for the treatment of postpartum anemia. STUDY DESIGN: We performed a retrospective cohort study with 210 anemic inpatient women in the postpartum period who received IV high-dose ICM (15 mg/kg; maximum, 1000 mg) or IS (2×200 mg), respectively. Safety and tolerability of both groups were compared on the basis of reported systemic and local adverse events. The cohorts were matched for baseline characteristics and their initial hemoglobin (Hb) values. The secondary endpoint included drug efficacy assessment by measurement of Hb level increase up to 8 days after treatment. RESULTS: Rapid administration of high ICM doses was as well tolerated as IS with overall adverse events of 5% (ICM) vs. 6% (IS). The most common complaint was burning and pain at the injection site. ICM was as effective as IS in changing Hb levels from the baseline. There was no difference in the mean daily Hb increase between the groups. Women with severe anemia showed the most effective responsiveness. CONCLUSIONS: IV ICM is as safe as IS in the management of postpartum (IDA) iron deficiency anemia despite five times of higher dosage. Both drugs are effective and offer a rapid normalization of Hb after delivery. The single application of ICM shows advantages of lower incidence of side effects at the injection site, a shorter treatment period, and better patient compliance.