Patient reported outcome measures and cardiovascular outcomes following high dose modern intravenous iron in non-dialysis dependent chronic kidney disease: secondary analysis of ExplorIRON-CKD.

Intravenous iron is commonly used to treat iron deficiency anemia in non-dialysis chronic kidney disease (ND-CKD). There is a paucity of information on the potential impact of intravenous iron on patient reported outcome measures, functional status and markers of cardiovascular health. As part of the secondary analysis of this double-blind exploratory randomized controlled trial focusing on patients with iron deficiency (+ /- anemia) and ND-CKD (serum ferritin < 200 µg/L or transferrin saturation ≤ 20% and serum ferritin 200-299 µg/L; CKD stages: 3a-5), 26 patients were randomized in a 1:1 ratio to receive ferric derisomaltose or ferric carboxymaltose. Participants received 1000 mg at baseline and 500-1000 mg at one month to achieve iron repletion. Quality of life and fatigue status were assessed using the Short-Form (36) questionnaire and the fatigue severity scale. Functional status was evaluated using the Duke Activity Status Index and the 1-min-sit-to-stand test. Cardiac markers such as NT-proBNP, Troponin T and pulse wave velocity were monitored. Intravenous iron was associated with similar improvements in most domains of the Short-Form (36) questionnaire, fatigue status, and 1-min-sit-to-stand ability increased significantly by the end of the trial in both groups (p < 0.001). Markers of cardiac function remained stable, with no arterial stiffness impact. Longer term studies are required to further evaluate the impact of intravenous iron on quality of life and cardiac safety in patients with ND-CKD.

A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD.

Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) µg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

High-dose intravenous iron reduces myocardial infarction in patients on haemodialysis.

AIMS: To investigate the effect of high-dose iron vs. low-dose intravenous (IV) iron on myocardial infarction (MI) in patients on maintenance haemodialysis. METHODS AND RESULTS: This was a pre-specified analysis of secondary endpoints of the Proactive IV Iron Therapy in Hemodialysis Patients trial (PIVOTAL) randomized, controlled clinical trial. Adults who had started haemodialysis within the previous year, who had a ferritin concentration <400 µg per litre and a transferrin saturation <30% were randomized to high-dose or low-dose IV iron. The main outcome measure for this analysis was fatal or non-fatal MI. Over a median of 2.1 years of follow-up, 8.4% experienced a MI. Rates of type 1 MIs (3.2/100 patient-years) were 2.5 times higher than type 2 MIs (1.3/100 patient-years). Non-ST-elevation MIs (3.3/100 patient-years) were 6 times more common than ST-elevation MIs (0.5/100 patient-years). Mortality was high after non-fatal MI (1- and 2-year mortality of 40% and 60%, respectively). In time-to-first event analyses, proactive high-dose IV iron reduced the composite endpoint of non-fatal and fatal MI [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.52-0.93, P = 0.01] and non-fatal MI (HR 0.69, 95% CI 0.51-0.93; P = 0.01) when compared with reactive low-dose IV iron. There was less effect of high-dose IV iron on recurrent MI events than on the time-to-first event analysis. CONCLUSION: In total, 8.4% of patients on maintenance haemodialysis had an MI over 2 years. High-dose compared to low-dose IV iron reduced MI in patients receiving haemodialysis. EUDRACT REGISTRATION NUMBER: 2013-002267-25.

Markers of Oxidative Stress, Inflammation and Endothelial Function following High-Dose Intravenous Iron in Patients with Non-Dialysis-Dependent Chronic Kidney Disease-A Pooled Analysis.

Chronic kidney disease (CKD) represents a state of oxidative stress imbalance, which is potentially amplified by iron deficiency. Intravenous iron is considered safe and efficacious in the treatment of iron deficiency anemia, however, concerns remain regarding its potential pro-oxidant effect, leading to inflammatory and endothelial consequences. This pooled analysis of two pilot randomized controlled trials aimed to group and analyze the potential effect of high-dose intravenous iron (ferric derisomaltose, 1000 mg) on markers of oxidative stress (thiobarbituric acid reactive substance), inflammation (C-reactive protein, interleukins 6 and 10) and endothelial response (E-selectin, P-selectin) in patients with non-dialysis-dependent CKD and iron deficiency with/without anemia. Pulse wave velocity as a surrogate measure of arterial stiffness was measured. Thirty-six patients were included. No statistically significant trend was identified for any of the aforementioned markers. Stratification and comparison of data based on CKD stage did not yield statistically significant trajectories with the exception of the C-reactive protein in CKD stage 3b. These results suggest that high-dose intravenous iron does not impact measures of oxidative stress or inflammation; however, the results are not conclusive. Further research in a larger cohort is necessary to characterize the effect of intravenous iron on oxidative status and inflammation and its potential sequela in CKD.

The effect of intravenous iron supplementation on exercise capacity in iron-deficient but not anaemic patients with chronic kidney disease: study design and baseline data for a multicentre prospective double-blind randomised controlled trial.

BACKGROUND: Many people living with chronic kidney disease (CKD) are iron deficient, even though they may not be anaemic. The Iron and Muscle study aims to evaluate whether iron supplementation reduces symptoms of fatigue, improves muscle metabolism, and leads to enhanced exercise capacity and physical function. We report here the trial design and baseline characteristics. METHODS: This is a prospective, double-blind multicentre randomised controlled trial (RCT) including 75 non-dialysis stage 3-4 CKD patients with iron deficiency but without anaemia. Patients were randomly (1:1) assigned to either: i) intravenous iron therapy, or ii) placebo, with concurrent recruitment of eight CKD non-iron deficient participants and six healthy volunteers. The primary outcome of the study is the six-minute walk test (6MWT) distance between baseline and four-weeks. An additional exercise training programme for patients in both groups was initiated and completed between 4 and 12 weeks, to determine the effect of iron repletion compared to placebo treatment in the context of patients undertaking an exercise programme. Additional secondary outcomes include fatigue, physical function, muscle strength, muscle metabolism, quality of life, resting blood pressure, clinical chemistry, safety and harms associated with the iron therapy intervention and the exercise training intervention, and hospitalisations. All outcomes were conducted at baseline, 4, and 12 weeks, with a nested qualitative study, to investigate the experience of living with iron deficiency and intervention acceptability. The cohort have been recruited and baseline assessments undertaken. RESULTS: Seventy-five individuals were recruited. 44% of the randomised cohort were male, the mean (SD) age was 58 (14) years, and 56% were White. Body mass index was 31 (7) kg/m2; serum ferritin was 59 (45) µg/L, transferrin saturation was 22 (10) %, and haemoglobin was 125 (12) g/L at randomisation for the whole group. Estimated glomerular filtration rate was 35 (12) mL/min/1.73 m2 and the baseline 6MWT distance was 429 (174) m. CONCLUSION: The results from this study will address a substantial knowledge gap in the effects of intravenous iron therapy, and offer potential clinical treatment options, to improve exercise capacity, physical function, fatigue, and muscle metabolism, for non-dialysis patients with CKD who are iron-deficient but not anaemic. It will also offer insight into the potential novel effects of an 8-week exercise training programme. TRIAL REGISTRATION: EudraCT: 2018-000,144-25 Registered 28/01/2019.

Impact of intravenous iron on cardiac and skeletal oxidative stress and cardiac mitochondrial function in experimental uraemia chronic kidney disease.

Introuction: Uraemia leads to changes in cardiac structure, metabolic remodeling and anaemia, key factors in the development of heart failure in patients with chronic kidney disease. Previous studies have identified abnormalities in mitochondrial function, potentially impairing energy provision and enhancing oxidative stress. This study characterised oxidant status and changes in mitochondrial function in uraemia and the impact of correcting anaemia via intravenous iron therapy. Methods: Experimental uraemia was induced in male Sprague-Dawley rats via a subtotal nephrectomy and parenteral iron administration given 6 weeks post-surgery. Oxidative stress from tissue samples was evaluated by measuring pro-oxidant activities and anti-oxidant capacities in both sham and uraemic animals with and without iron supplementation. Thiobarbituric acid-reactive substances (TBARS), aconitase activity and cardiolipin were measured. Mitochondrial function was assessed using the Seahorse XFp analyser on isolated mitochondria excised from cardiac tissue. Results: Oxidative stress in this uraemic model was increased in cardiac tissue (increased GSSG/GSH ratio, TBARS and increased activities of pro-oxidant enzymes). There was no impact on skeletal tissue. Parenteral iron ameliorated oxidative stress by enhancing the anti-oxidant defense system in cardiac tissue and skeletal tissue. Examination of respiratory reserve in cardiac mitochondria demonstrated that parenteral iron restored mitochondrial function. This experimental model of uraemia demonstrated a specific oxidative stress on the heart muscle without significant changes in skeletal oxidant status. Iron therapy improved anti-oxidant defence system, consequently reducing oxidative stress in the heart and skeletal tissue. There was an improvement in cardiac mitochondrial function. Conclusions: This experimental evidence indicates that iron therapy could reduce vulnerability to oxidative stress and potentially improve both cardiac and skeletal functional capacity from improvements in mitochondrial function.

Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure.

Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

OBJECTIVES: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients. BACKGROUND: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat. METHODS: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial. RESULTS: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event. CONCLUSIONS: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).

The comparative effects of intravenous iron on oxidative stress and inflammation in patients with chronic kidney disease and iron deficiency: a randomized controlled pilot study.

BACKGROUND: Concerns exist regarding the pro-oxidant and inflammatory potential of intravenous (IV) iron due to labile plasma iron (LPI) generation. This IRON-CKD trial compared the effects of different IV irons on oxidative stress and inflammation. METHODS: In this randomized open-label explorative single-center study in the United Kingdom, non-dialysis-dependent chronic kidney disease (CKD) patients with iron deficiency were randomized (1:1:1:1) to receive a single infusion of 200 mg iron dextran, or 200 mg iron sucrose (IS), or 200 mg or 1,000 mg ferric derisomaltose (FDI) and were followed up for 3 months. The primary outcomes measured were induction of oxidative stress and inflammation. Secondarily, efficacy, vascular function, quality of life, and safety were monitored. RESULTS: Forty patients were enrolled. No significant rise in oxidative stress existed, regardless of preparation or dose. There was a significant rise in LPI with 1,000 mg FDI at 2 hours that normalized within a week, not impacting oxidative stress or inflammation. A delayed rise in C-reactive protein was noted with IS. High-dose FDI produced a sustained serum ferritin increase (mean ± standard error of the mean of predose: 69.1 ± 18.4 µg/L, 3 months: 271.0 ± 83.3 µg/L; p = 0.007). Hemoglobin remained stable throughout. No adverse drug reactions were recorded during the study. CONCLUSION: A single dose of IV iron in CKD patients does not trigger oxidative stress or inflammation biomarkers. Third-generation IV irons have a reassuring safety profile, and high-dose FDI produced a sustained serum ferritin rise and more efficient iron repletion, with no significant pro-oxidant or inflammatory signals when compared to a lower dose and other IV irons.

Stroke in Hemodialysis Patients Randomized to Different Intravenous Iron Strategies: A Prespecified Analysis from the PIVOTAL Trial.

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared with similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized, controlled trial of intravenous iron treatment strategies in HD. Methods: We analyzed data from the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, focusing on variables associated with risk of stroke. The trial randomized 2141 adults who had started HD <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA) to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke. Results: During a median 2.1 years of follow-up, 69 (3.2%) patients experienced a first postrandomization stroke. Fifty-seven (82.6%) were ischemic strokes, and 12 (17.4%) were hemorrhagic strokes. There were 34 postrandomization strokes in the proactive arm and 35 postrandomization strokes in the reactive arm (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.44; P=0.66). In multivariable models, women, diabetes, history of prior stroke at baseline, higher baseline systolic BP, lower serum albumin, and higher C-reactive protein were independently associated with stroke events during follow-up. Hemoglobin, total iron, and ESA dose were not associated with risk of stroke. Fifty-eight percent of patients with a stroke event died during follow-up compared with 23% without a stroke. Conclusions: In patients on HD, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.Clinical Trial registry name and registration number: Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), 2013-002267-25.

An evaluation of ferric derisomaltose as a treatment for anemia.

Introduction: Originally approved in Europe in 2009, ferric derisomaltose is the most recently authorized intravenous iron compound in the United States of America (2020). Ferric derisomaltose given as a rapid high-dose infusion can allow complete iron repletion in a single dose and it is now widely used in the treatment of iron deficiency. Areas covered: The chemistry, pharmacodynamics and pharmacokinetics of ferric derisomaltose are reviewed. Results from phase II, III and IV trials regarding efficacy and safety are presented. Mechanisms behind minor infusion reactions, hypersensitivity and hypophosphatemia are discussed. The economic impact of ferric derisomaltose use is presented. Data pertaining to the use of ferric derisomaltose in iron deficiency anemia, chronic kidney disease, inflammatory bowel disease, chronic heart failure, perioperative care and other patient groups are comprehensively covered. Expert opinion: Ferric derisomaltose is an effective intravenous iron formulation with a good safety profile, providing rapid, cost-effective iron repletion. Ferric derisomaltose releases low quantities of labile iron relative to older compounds. Anaphylaxis is extremely rare, and 'Fishbane' reactions are uncommon. Hypophosphatemia following ferric derisomaltose administration is infrequent in comparison to other intravenous irons such as ferric carboxymaltose. The scope of ferric derisomaltose use is growing with increasing research in these areas.

Protocol and Baseline Data of a Multicentre Prospective Double-Blinded Randomized Study of Intravenous Iron on Functional Status in Patients with Chronic Kidney Disease.

BACKGROUND: Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) due to an inadequate dietary intake of iron, poor absorption from the gut and increased iron losses. In addition to preventing anaemia, iron is important for normal heart function, being involved in processes that generate a necessary continuous energy supply. Treatment with intravenous (IV) iron has been suggested to lead to improvement in heart function and well-being in people with ID and CKD. In the Iron and the Heart Study, we hypothesized that IV iron treatment will primarily improve exercise capacity and may secondarily impact the feeling of well-being in comparison to placebo over 3 months in non-anaemic CKD patients who have ID. METHODS: This was a prospective double-blinded explorative randomized, multi-centre study designed to compare the effects of IV iron supplementation and placebo in iron-deficient but not anaemic patients with established CKD stages 3b-5 on functional status, and in addition cardiac structure and function. The study included 54 adults with serum ferritin (SF) <100 µg/L and/or transferrin saturation <20%, randomized in a 1:1 ratio to 1,000 mg IV ferric derisomaltose or placebo. Following randomization, participants underwent baseline assessments and then received IV iron or placebo infusion. Each participant was followed up at months 1 and 3. At each visit, patients underwent clinical review, measurements of hematinics and haemoglobin (Hb), and assessments of physical function and well-being. The primary outcome was exercise capacity using the 6-minute walk test. Secondary objectives included effects on hematinic profiles and Hb concentration, changes in myocardial parameters assessed with speckle tracking echocardiography and change in patients' quality of life. RESULTS: Between October 2016 and April 2018, 55 from 326 individuals from 3 UK centres attended screening and were randomized. The mean (SD) age was 59.6 (11.7) years, 26 (48%) patients were male, the majority were Caucasians (42; 78%), and 32 (59%) were non-smokers. The mean (SD) body mass index was 30.3 (6.5); SF was 66.3 (44.1) µg/L, TS was 20.1 (7.4) % and Hb was 128.7 (10.1) g/L at randomization for the whole group. Mean (SD) serum creatinine was 186.7 (58.6) µmol/L, estimated glomerular filtration rate was 31.1 (9.6) mL/min/1.73 m2 and urinary albumin and protein/creatinine ratios 60.9 (133.3) and 83.8 (128.4) mg/mmol respectively. The mean (SD) C-reactive protein was 5.0 (4.4) mg/L and the mean (SD) 6-minute walk distance at baseline was 401.2 (120.2) m. CONCLUSION: The Iron and the Heart Trial will provide important information on the short-term effects of IV iron treatment in CKD patients with ID without anaemia on measures of exercise capacity, quality of life and mechanistic data on myocardial structure and function. TRIAL REGISTRATION: European Clinical Trials Database (No. 2014-004133-6; REC no. 14/YH/1209; Sponsor ref. R1766).

Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial.

BACKGROUND: Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis. METHODS: Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter). RESULTS: We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes. CONCLUSIONS: The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND: Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited. METHODS: In a multicenter, open-label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 µg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 µg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25. RESULTS: A total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, -7539 IU; 95% confidence interval [CI], -9485 to -5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups. CONCLUSIONS: Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25 .).

Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data.

BACKGROUND: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. METHODS: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 µg/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. RESULTS: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. CONCLUSIONS: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. TRIAL REGISTRATION: EudraCT number: 2013-002267-25.

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.

Anemia in Peritoneal Dialysis Patients; Iron Repletion, Current and Future Therapies.

Iron deficiency, both functional and absolute, is common in patients with chronic kidney disease (CKD), especially those requiring dialysis. Guidelines advocate treatment of iron-deficiency anemia in patients with CKD and those on peritoneal dialysis (PD). Oral iron is often insufficient and slow to improve hemoglobin concentrations because of high hepcidin levels causing impaired absorption and mobilization, while intravenous (IV) supplementation replenishes and maintains iron stores more effectively and is now standard practice (Kidney Disease Improving Global Outcomes [KDIGO] 2012 guidelines). However, there still remain concerns about the effects of labile iron and possible increased risk of infections for this group of patients.To date, the majority of published studies have focused on hemodialysis (HD) patients; very limited data are available regarding patients on PD. This review summarizes the rationale for iron therapy, methods of treatment, potential adverse effects, and long-term concerns in PD patients. In addition we highlight some interesting potential future therapies under study.

Efficacy and safety of iron isomaltoside (Monofer(®)) in the management of patients with iron deficiency anemia.

New intravenous (IV) iron preparations should ideally be capable of delivering a wide dosing range to allow iron correction in a single or low number of visits, a rapid infusion (doses up to 1,000 mg must be administered over more than 15 minutes and doses exceeding 1,000 mg must be administered over 30 minutes or more), and minimal potential side effects including low catalytic/labile iron release with minimal risk of anaphylaxis. Furthermore, they should be convenient for the patient and health-care professional, and cost effective for the health-care system. The intention behind the development of iron isomaltoside (Monofer(®)) was to fulfill these requirements. Iron isomaltoside has been shown to be effective in treating iron deficiency anemia across multiple therapeutic patient groups and compared to placebo, IV iron sucrose, and oral iron. Iron isomaltoside consists of iron and a carbohydrate moiety where the iron is tightly bound in a matrix structure. It has a low immunogenic potential, a low potential to release labile iron, and does not appear to be associated with clinically significant hypophosphatemia. Due to the structure of iron isomaltoside, it can be administered in high doses with a maximum single dosage of 20 mg/kg body weight. Clinical trials and observational studies of iron isomaltoside show that it is an effective and well-tolerated treatment of anemia across different therapeutic areas with a favorable safety profile.

Correlation of iron overload and glomerular filtration rate estimated by cystatin C in patients with ß-thalassemia major.

Historically, renal involvement has not been a commonly recognized complication in patients with ß-thalassemia major (ß-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with ß-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3 ± 9 years (range 2.5-38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient -0.25). In the univariable analyses, serum ferritin (p = 0.004), diabetes status (p < 0.001) and chelation therapy (p < 0.001) were statistically significant. In the multivariable model, age (p = 0.033), chelation with DFX (p = 0.05) and diabetes status (p < 0.001) were statistically significant. We found a very weak inverse linear correlation between serum ferritin and Cyst C eGFR. However, when concomitant use of chelation therapy was considered, serum ferritin did not associate with glomerular function. Prospective and larger studies are needed to confirm these findings.