Iron Administration In Patients Research Articles

Intravenous iron administration in patients with heart failure alters endothelial homeostasis with early release of endothelial microvesicles and subsequent mobilization of endothelial progenitor cell

Abstract Background Intravenous iron supplementation is an established therapy for patients with heart failure (HF) with reduced ejection fraction (LV-EF<50%) and iron deficiency, resulting in reduced risk of HF hospitalization. Since iron may induce oxidative stress, inflammation and apoptosis in endothelial cells, concerns persist regarding potential adverse vascular effects of iron therapy. To evaluate endothelial health following ferric carboxymaltose (FCM) administration, we assessed the profile of circulating endothelial microvesicles (EMVs) and endothelial progenitor cells (EPCs) in a cohort of 23 HF patients using flow cytometry. Results Compared to healthy control subjects (HC; n=15), baseline levels of CD31+/CD41- EMVs were significantly higher and EMVs featured a more apoptotic phenotype in HF patients. Following administration of 1000mg FCM, EMV levels showed an early but transient increase (Fig. 1) and displayed an altered phenotype profile with dominant augmentation of EMVs expressing the inducible markers CD62E and CD54, indicating endothelial activation and injury. Levels of circulating vasoregenerative CD45lowCD34+KDR+ EPCs were lower in HF patients and FCM application resulted in an early decrease of EPCs followed by substantial mobilization into the circulation after one week (Fig. 2). Levels of EMVs and EPCs returned to baseline values within two and four weeks, respectively. Compared to HF patients with preserved renal function, the EMV/EPC ratio was higher in HF patients whereas EPC mobilization was diminished with additional chronic kidney disease, suggesting impaired vascular repair capacity. In vitro experiments with cultured endothelial cells revealed that FCM at therapeutic concentrations dose-dependently promotes endothelial apoptosis, increases expression of adhesion molecules and CXCL12, and triggers the generation of EMVs. Conclusion Intravenous iron supplementation with FCM in HF patients provokes a biphasic response with early release of CD62E+ and CD54+ enriched EMVs and subsequent mobilization of EPCs, suggesting temporary aggravation of endothelial dysfunction upon FCM supplementation and consecutive engagement of a vascular defense program.

Intravenous iron therapy among patients with heart failure and iron deficiency: An updated meta-analysis of randomized controlled trials

BackgroundRandomized clinical trials (RCTs) evaluating the role of intravenous (IV) iron administration in patients with heart failure (HF) and iron deficiency (ID) have yielded inconsistent results. MethodsElectronic search of MEDLINE, EMBASE and OVID databases was performed until November 2022 for RCTs that evaluated the role of IV iron administration in patients with HF and ID. The main study outcomes were the composite of HF hospitalization or cardiovascular mortality, and individual outcome of HF hospitalization. Summary estimates were evaluated using random effects model. ResultsThe final analysis included 12 RCTs with 3,492 patients (1,831 patients in the IV iron group and 1,661 patients in the control group). The mean follow-up was 8.3 months. IV iron was associated with a lower incidence in the composite of HF hospitalization or cardiovascular mortality (31.9% vs. 45.3%; relative risk [RR] 0.72; 95% confidence interval [CI] 0.59–0.88) and individual outcome of HF hospitalization (28.4% vs. 42.2; RR 0.69; 95% CI 0.57–0.85). There was no significant difference between both groups in cardiovascular mortality (RR 0.88; 95% CI 0.75–1.04) and all-cause mortality (RR 0.95; 95% CI 0.83–1.09). IV iron was associated with lower New York Heart Association class and higher left ventricular ejection fraction (LVEF). Meta-regression analyses showed no effect modification for the main outcomes based on age, hemoglobin level, ferritin level or LVEF. ConclusionAmong patients with HF and ID, IV iron administration was associated with reduction in the composite of HF hospitalization or cardiovascular mortality and driven by a reduction in HF hospitalization.

MO546THE SHORT-TERM EFFECT OF HIGH DOSE THIRD GENERATION INTRAVENOUS IRON ON PATIENTS IN PATIENTS WITH CKD AND IRON DEFICIENCY ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIUM AND MYOCARDIAL STRESS

Abstract Background and Aims Intravenous (IV) iron administration in patients with chronic kidney disease (CKD) may lead to both pro-oxidant and pro-inflammatory effects and thus secondarily compromise, potentially causing adverse cardiovascular outcomes. In-vitro and in-vivo studies suggest that these effects correlate with the amount of labile free iron circulating following infusion of iron. Third generation IV irons (e.g. ferric derisomaltose (FDI)) have been developed with more compact iron-carbohydrate cores, enabling higher doses to be delivered in a single sitting with lower labile iron generation. The Iron & Heart study was a multicentre randomized placebo-controlled trial set out to examine the effect of high dose third generation iron (FDI) on the functional capacity of patients with CKD and iron deficiency. A pre-specified secondary mechanistic endpoint was the effect of FDI on markers of oxidative stress, inflammation, endothelial function and cardiac stress. Method This was a multicentre double blinded randomized placebo-controlled trial in three tertiary renal centres in the United Kingdom. Patients with CKD stages 3b-5 (non-dialysis) and iron deficiency without anaemia (serum ferritin <100 micrograms/L and/or transferrin saturation <20%) were enrolled. The participants were randomized 1:1 to receive either 1000 mg of FDI or placebo and followed up at 1- and 3-month intervals. Biomarkers of inflammation (CRP, IL6, IL8 and IL10), oxidative stress (thiobarbituric acid reactive substances and F2-isoprostane) and cardiac stress (NT-proBNP) were analysed. Endothelial function was investigated through biomarkers (E-selectin and P-selectin) and pulse wave velocity measurements. Statistical analysis using repeated measure ANOVA with baseline, 1 month and 3-month data was performed with statistical significance inferred at p<0.05. Results A total of 54 patients were randomized to receive FDI (n=26) or placebo (n=28). The two groups were comparable for baseline characteristics. Both pro and anti-inflammatory cytokines (IL2, IL6 and IL10) were not affected by FDI at any study point, nor there was any statistical difference was exhibited in CRP (FDI vs. placebo: 1-month: 4.2 (2.7) vs. 6.9 mg/L (18.3), p=0.6; 3-months: 7.5 (6.8) vs. 10.3 mg/L (23.0); p=0.46). Markers of oxidative stress were not significantly altered following FDI treatment or in comparison to placebo. A non-significant trend for a decrease in F2-isoprostane measurements was noted during the first month following FDI infusion compared to placebo (-77% vs. -66%; p=0.83). FDI caused a greater reduction in NT-proBNP compared to placebo (FDI: baseline: 422 (881.9) ng/l; 1-month: 242.5 (209.1) ng/l; placebo: baseline: 485.2 (1268.1) ng/l; 1-month: 436.4 (1383.4) ng/l), but this was not statistically significant (p=0.37). Pulse wave velocity was not affected in either group while measurements of P-selectin remained unaltered. There was a statistically significant increase in E-selectin at both follow-up points following infusion with FDI compared with placebo (1-month: p=0.03; 3 months: p<0.001). Conclusion High dose third generation iron treatment of CKD patients with iron deficiency did not lead to either a pro-oxidant or a pro-inflammatory signal. The decrease in markers of oxidative stress following administration of FDI may represent the anti-oxidant effects following alleviation of iron deficiency. Although there was no increase in inflammatory markers there was an increase in E-selectin which might impact vascular function, as upregulation of selectins can be a sign of inflammation or atherosclerosis but the unaffected pulse wave velocity and the reduction in NT pro-BNP are reassuring. Overall, the data confirm that high dose FDI therapy is mechanistically safe. Further larger studies are needed to confirm these findings and the longer term impact on cardiac and vascular function of high dose FDI administration.

Iron supplementation for patients undergoing cardiac surgery: a protocol for a systematic review and meta-analysis of randomized controlled trials.

Background:Iron administration has been evaluated in several randomized controlled trials for the potential of increasing baseline hemoglobin values and decreasing the incidence of red blood cell transfusion during cardiac surgery. We describe the protocol for a study aiming to evaluate the efficacy and safety of perioperative iron administration in patients undergoing cardiac surgery.Methods:We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science, from inception to Nov. 19, 2020, for randomized controlled trials in any language evaluating the perioperative administration of iron in adult patients undergoing cardiac surgery; we will also include the first 50 results from Google Scholar. The primary outcome will be the incidence of red blood cell transfusion from the study intervention time until 8 weeks postoperatively. The secondary outcomes will be the number of red blood cell units transfused; change in ferritin level, reticulocyte count and hemoglobin concentration after iron administration; and adverse events. We will assess the risk of bias with the Cochrane Collaboration Risk of Bias Tool, and will analyze the primary and secondary outcomes using a random-effects model.Interpretation:This study will summarize the current evidence about perioperative iron administration in patients undergoing cardiac surgery, help determine whether this intervention should be included in enhanced-recovery protocols, and shape future research if needed. The final manuscript will be submitted to a peer-reviewed journal. Trial registration:PROSPERO no. CRD42020161927

DOP63 Efficacy and safety of iron carboxymaltose on chronic fatigue in patients with inflammatory bowel disease: a randomised controlled trial

Abstract Background Patients with inflammatory bowel diseases (IBD) have an altered quality of life, also due to chronic fatigue (CF). Iron administration is effective in iron deficiency associated with CF in patients with heart failure. Our hypothesis was that iron administration in patients with iron-deficiency could improve CF and quality of life in IBD patients. Methods This was a phase 2, randomised, placebo-controlled, double-blind trial. Adult patients with established IBD diagnosis in clinical remission (HB <5; Mayo clinical score ≤2) from ≥ 6 months, CF symptoms (MFI-20> 13), martial deficiency (ferritin <100 µg/l, or <300 µg/l if transferrin saturation<20%), but not anaemia, were eligible. Patients were randomised to receive 200 mg of i.v. iron carboxymaltose (ICM) or placebo (PBO) every month up to 6 months. The primary objective was to compare the rate of patients in CF remission (Multidimensional Fatigue Inventory, MFI-20 <13) between the 2 groups. Secondary objectives were CF response (MFI-20 decrease of ≥4 points, but MFI-20 total >13) at week 24 and CF remission (MFI-20 <13) at week 12. Evolution of anxiety and depression and change in the quality of life at weeks 4, 12 and 24 from baseline trough week 24 were also assessed. The calculated sample size was 36 patients (18 for each treatment arm). Results Forty-six patients were screened, 30 patients completed 24 weeks of treatment (21 Crohn’s disease, 9 ulcerative colitis). Baseline characteristics were not different among the two groups. Between patients treated with ICM vs. PBO, 2/15 patients vs. 0/15 respectively were in CF remission at week 24 (13% vs. 0%, p = 0.46). CF response was observed in 7/15 patients treated with ICM vs. 10/15 patients with PBO (47% vs. 67%, p = 0.46). At week 12, 1/17 vs. 0/17 patients were in CF remission (6% vs. 0%, p = 0.96), and 12/17 vs. 10/17 (71% vs. 59%, p = 0.90) showed CF response. At the study completion, ferritin restoration was found in 12/14 patients (86%) treated with ICM vs. 1/15 (7%) receiving PBO (p < 0.001). No significant differences in terms of anxiety, depression and quality of life restoration were found between the two groups at week 12 and 24. A total number of 69 adverse events (AEs) were reported in 17 patients (37 mild, 31 moderate, 1 severe), only 5 were related to the study treatment (3 nausea, 1 gastric pain, 1 arthralgia), and only 1 (nausea) led to study drug discontinuation. Conclusion Intravenous ICM is not effective in treating CF in IBD patients, with no significant adverse events. ICM was more effective than PBO in restoring ferritin in the majority of IBD patients. Funding This study was funded by the ECCO Vifor Grant 2017.

Is there any role of intravenous iron for the treatment of anemia in cancer?

BackgroundAnemia is a major cause of morbidity in patients with cancer resulting in poor physical performance, prognosis and therapy outcome. The aim of this study is to assess the efficacy of intravenous (iv) iron administration for the correction of anemia, for the prevention of exacerbation of anemia, for decreasing blood transfusion rates, and for the survival of cancer patients.MethodsPatients with different solid tumor diagnosis who received iv iron during their cancer treatment were evaluated retrospectively. Sixty-three patients with hemoglobin (Hgb) levels between ≥ 9 g/dL, and ≤ 10 g/dL, and no urgent need for red blood cell transfusion were included in this retrospective analysis. The aim of cancer treatment was palliative for metastatic patients (36 out of 63), or adjuvant or curative for patients with localized disease (27 out of 63). All the patients received 100 mg of iron sucrose which was delivered intravenously in 100 mL of saline solution, infused within 30 min, 5 infusions every other day. Complete blood count, serum iron, and ferritin levels before and at every 1 to 3 months subsequently after iv iron administration were followed regularly.ResultsInitial mean serum Hgb, serum ferritin and serum iron levels were 9.33 g/dL, 156 ng/mL, and 35.9 μg/dL respectively. Mean Hgb, ferritin, and iron levels 1 to 3 months, and 6 to 12 months after iv iron administration were 10.4 g/dL, 11.2 g/dL, 298.6 ng/mL, 296.7 ng/mL, and 71.6 μg/dL, 67.7 μg/dL respectively with a statistically significant increase in the levels (p < 0.001). Nineteen patients (30 %) however had further decrease in Hgb levels despite iv iron administration, and blood transfusion was necessary in 18 of these 19 patients (28.5 %). The 1-year overall survival rates differed in metastatic cancer patients depending on their response to iv iron; 61.1 % in responders versus 35.3 % in non-responders, (p = 0.005), furthermore response to iv iron correlated with tumor response to cancer treatment, and this relation was statistically significant, (p < 0.001).ConclusionsIv iron administration in cancer patients undergoing active oncologic treatment is an effective and safe measure for correction of anemia, and prevention of worsening of anemia. Amelioration of anemia and increase in Hgb levels with iv iron administration in patients with disseminated cancer is associated with increased tumor response to oncologic treatment and overall survival. Response to iv iron may be both a prognostic and a predictive factor for response to cancer treatment and survival.

Effects of Total Dose Infusion of Iron Intravenously in Patients With Acute Heart Failure and Anemia (Hemoglobin < 13 g/dl)

Iron deficiency is common in heart failure (HF), and intravenous (IV) iron therapy has been associated with improved clinical status in ambulatory patients with HF. There are limited data to support the safety and efficacy of IV iron administration in patients with acute HF. This was a retrospective cohort study of patients admitted to the University of Michigan Health System for HF with low iron studies during admission. Patients were grouped based on the receipt of IV iron therapy. Study outcomes included change in hemoglobin, 30-day readmission, and adverse events. Forty-four patients who received IV iron and 128 control patients were identified. The mean dose of IV iron received was 1,057 (±336) mg. IV iron resulted in a significantly greater increase in hemoglobin over time (p= 0.0001). The mean change in hemoglobin in the iron and control groups was 0.74g/dl and 0.01g/dl at day 7 and 2.61g/dl and 0.23g/dl at day 28, respectively. Thirty-day readmission rates were 30% and 22% for patients in the iron and control groups, respectively (p= 0.2787). In conclusion, total dose infusion IV iron is well tolerated and associated with significant improvement in hemoglobin in acute HF.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long-term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations.

Iron deficiency and cardiovascular disease

Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

Inflammation, high ferritin, and erythropoietin resistance in indigenous maintenance hemodialysis patients from the Top End of Northern Australia.

Use of erythropoiesis-stimulating agents (ESAs) has improved the management of anemia in patients on maintenance hemodialysis (MHD). Iron deficiency and inflammation cause ESAs resistance and are both common among indigenous people of Northern Australia. As part of quality assurance in our Renal Anaemia Management program, we observed that there was use of higher doses of ESAs and adjuvant iron therapy in our MHD patients. This study aimed to explore the relationship among iron studies, inflammation, ESA responsiveness, and ESAs and iron requirements in indigenous patients on MHD from the Top End of Northern Australia. We performed a retrospective cohort analysis of anemia management in a cohort of our patients on MHD. We extracted data for 178 indigenous and 19 non-indigenous patients from 1 March 2009 to 28 February 2010 from the Renal Anaemia Management database, which collects data prospectively in MHD patients. Ninety-nine percent of the whole sample had a ferritin level above the international guidelines threshold of >500 µg/L. Indigenous patients had higher ferritin (1534 ± 245.5 µg/L vs. 1013 ± 323.3 µg/L, P = 0.002). C-reactive protein (CRP) was high in 56.9% of the total cohort. One hundred percent of those with normal CRP had high ferritin (>500 µg/L). C-reactive protein was higher in indigenous than in non-indigenous patients. Erythropoiesis-stimulating agents hyporesponsiveness was higher in indigenous patients (P < 0.0001). There was no significant difference in ESAs hyporesponsiveness among different levels of CRP (P = 0.116), ferritin (P = 0.408), and transferrin saturation (P = 0.503). Indigenous patients required higher total iron dose (2820.30 [2000-4350] vs. 2336.12 [1912-2900], P = 0.02). There was no significant relationship between the high ferritin and CRP. In indigenous dialysis patients, iron therapy and ESAs use are higher. The high iron use is due to a lack of published evidence to guide the administration of iron in patients with high ferritin. The high ferritin and ESAs resistance could not be fully explained by inflammation and need further evaluation. Further studies are required to determine the safe use of iron and management of ESAs resistance in our hemodialysis population.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of "acceptability" that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children.

P123 Use of soluble transferrin receptor/log10 ferritin index as a predictor of response to intravenous iron administration in patients with inflammatory bowel disease and anemia

P123 Use of soluble transferrin receptor/log10 ferritin index as a predictor of response to intravenous iron administration in patients with inflammatory bowel disease and anemia

Iron, oxidative stress, and clinical outcomes

It is well known that iron is pro-oxidant. Chronic kidney disease (CKD) is a pro-oxidant state, and intravenous administration of iron is frequently used to correct anemia. On one hand, there is little doubt that iron causes oxidative stress. On the other, it is far from clear whether oxidative stress, so generated, leads to poor clinical outcomes. Iron has benefits that may be independent of the correction of anemia. Furthermore, concerns surround the use of high doses of erythropoietin in causing excess heart failure and death in patients with CKD. Thus, it would be prudent if iron were to continue to be used judiciously in patients who require erythropoietin. Iron, given orally, would be the preferred first-line agent in patients not on hemodialysis. In patients with sepsis, intravenous treatment with iron should be avoided, because, in animal experiments, intravenous administration of iron can compound the inflammatory response and increase mortality. Clinical trials are needed to ascertain the risk and benefits of the intravenous administration of iron in patients with CKD.

Increased Hemolysis after Intramuscular Iron Administration in Patients with Paroxysmal Nocturnal Hemoglobinuria: Report of Six Occurrences in Four Patients, and Speculations on a Possible Mechanism

Abstract Four patients with PNH were described who developed accelerated activity of their disease after the intramuscular administration of iron-dextran for treatment of iron deficiency. This was considered to reflect a unique effect of iron on PNH erythrocytes. It was postulated that this effect resulted from cell damage caused by iron catalyzed peroxidation of erythrocyte lipids, a reaction to which PNH erythrocytes could be unusually susceptible by virtue of an increased content of unsaturated fatty acids or pro-oxidants or decreased content of antioxidants.