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Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial.
Shah, A, Chester-Jones, M, Dutton, SJ, Marian, IR, Barber, VS, Griffith, DM, Singleton, J, Wray, K, James, T, Drakesmith, H, et al
British journal of anaesthesia. 2022;(2):272-282
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Abstract
BACKGROUND Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear. METHODS We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L-1). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes. RESULTS Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L-1) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L-1), adjusted mean difference (10.98 g L-1; 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15). CONCLUSION A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes. CLINICAL TRIAL REGISTRATION ISRCTN13721808 (www.isrctn.com).
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Association of fibroblast growth factor 23 and α-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study.
Ito, K, Yokoyama, K, Nakayama, M, Fukagawa, M, Hirakata, H
BMC nephrology. 2021;(1):374
Abstract
BACKGROUND Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. METHODS The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted. RESULTS Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p < 0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): - 0.2 ± 0.8 loge pg/mL vs. 0.2 ± 0.8 loge pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: - 0.1 ± 0.8 loge pg/mL vs. 0.1 ± 0.9 loge pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. - 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups. CONCLUSIONS Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained. TRIAL REGISTRATION ASTRIO study ( UMIN000019176 , registered at UMIN Clinical Trials Registry on October 1, 2015).
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Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.
Bhandari, S, Kalra, PA, Berkowitz, M, Belo, D, Thomsen, LL, Wolf, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2021;(1):111-120
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Abstract
BACKGROUND The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. METHODS In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). RESULTS A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. CONCLUSIONS Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.
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The IHAT-GUT Iron Supplementation Trial in Rural Gambia: Barriers, Facilitators, and Benefits.
Stelle, I, McDonagh, LK, Hossain, I, Kalea, AZ, Pereira, DIA
Nutrients. 2021;(4)
Abstract
INTRODUCTION In most sub-Saharan African countries iron deficiency anaemia remains highly prevalent in children and this has not changed in the last 25 years. Supplementation with iron hydroxide adipate tartrate (IHAT) was being investigated in anaemic children in a phase two clinical trial (termed IHAT-GUT), conducted at the Medical Research Council Unit the Gambia at the London School of Hygiene and Tropical Medicine (LSHTM) (abbreviated as MRCG hereof). This qualitative study aimed to explore the personal perceptions of the trial staff in relation to conducting a clinical trial in such settings in order to highlight the health system specific needs and strengths in the rural, resource-poor setting of the Upper River Region in the Gambia. METHODS Individual interviews (n = 17) were conducted with local trial staff of the IHAT-GUT trial. Data were analysed using inductive thematic analysis. RESULTS Potential barriers and facilitators to conducting this clinical trial were identified at the patient, staff, and trial management levels. Several challenges, such as the rural location and cultural context, were identified but noted as not being long-term inhibitors. Participants believed the facilitators and benefits outnumbered the barriers, and included the impact on education and healthcare, the ambitious and knowledgeable locally recruited staff, and the local partnership. CONCLUSIONS While facilitators and barriers were identified to conducting this clinical trial in a rural, resource-poor setting, the overall impact was perceived as beneficial, and this study is a useful example of community involvement and partnership for further health improvement programs. To effectively implement a nutrition intervention, the local health systems and context must be carefully considered through qualitative research beforehand.
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Nanoparticles in the Food Industry and Their Impact on Human Gut Microbiome and Diseases.
Ghebretatios, M, Schaly, S, Prakash, S
International journal of molecular sciences. 2021;(4)
Abstract
The use of inorganic nanoparticles (NPs) has expanded into various industries including food manufacturing, agriculture, cosmetics, and construction. This has allowed NPs access to the human gastrointestinal tract, yet little is known about how they may impact human health. As the gut microbiome continues to be increasingly implicated in various diseases of unknown etiology, researchers have begun studying the potentially toxic effects of these NPs on the gut microbiome. Unfortunately, conflicting results have limited researcher's ability to evaluate the true impact of NPs on the gut microbiome in relation to health. This review focuses on the impact of five inorganic NPs (silver, iron oxide, zinc oxide, titanium dioxide, and silicon dioxide) on the gut microbiome and gastrointestinal tract with consideration for various methodological differences within the literature. This is important as NP-induced changes to the gut could lead to various gut-related diseases. These include irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), celiac disease, and colorectal cancer. Research in this area is necessary as the use of NPs in various industries continues to grow along with the number of people suffering from chronic gastrointestinal diseases.
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Using iron-based phosphate binders in phosphate reduction and anemia improvement in patients receiving dialysis: a meta-analysis of randomized controlled trials.
Zhu, Y, Rao, J, Liao, X, Ou, J, Li, W, Xue, C
International urology and nephrology. 2021;(9):1899-1909
Abstract
PURPOSE A study was conducted to determine whether iron-based phosphate binders (IBPBs) need to be preferred for hyperphosphatemia and anemia management in patients on dialysis. METHODS For this meta-analysis, we searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled trials that evaluated the efficacy and safety of IBPBs in decreasing phosphate and correcting anemia in dialysis patients. RESULTS Nineteen trials comprising 4719 participants were included. Compared with placebo, serum phosphate decreased significantly after treatment with ferric citrate (FC), fermagate (one study), and SBR759 (one study). Hemoglobin increased significantly after treatment with FC and sucroferric oxyhydroxide (PA21). In addition, FC and PA21 reduced serum intact parathyroid hormone (iPTH) and increased ferritin and transferrin saturation, but SBR759 did not. Compared with active treatment, the non-inferiority of IBPBs in reducing serum phosphate and iPTH was demonstrated. FC significantly improved serum hemoglobin and iron-related parameters and decreased the use of intravenous iron and erythropoiesis-stimulating agent, whereas PA21 did not increase serum hemoglobin level. The incidences of infection and hospitalization were similar between the two groups, with FC having a higher risk of diarrhea than the placebo and active treatments. CONCLUSION FC was associated with the control of hyperphosphatemia and the improvement of anemia. However, PA21 did not show superiority for alleviating anemia compared with the active treatment. Other IBPBs, such as fermagate and SBR759, remained poorly understood due to the limited number of studies. Further trials are required to assess the effect of IBPBs on the risk of cardiovascular events and all-cause mortality.
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Myocardial inflammation and energetics by cardiac MRI: a review of emerging techniques.
Tsampasian, V, Swift, AJ, Assadi, H, Chowdhary, A, Swoboda, P, Sammut, E, Dastidar, A, Cabrero, JB, Del Val, JR, Nair, S, et al
BMC medical imaging. 2021;(1):164
Abstract
The role of inflammation in cardiovascular pathophysiology has gained a lot of research interest in recent years. Cardiovascular Magnetic Resonance has been a powerful tool in the non-invasive assessment of inflammation in several conditions. More recently, Ultrasmall superparamagnetic particles of iron oxide have been successfully used to evaluate macrophage activity and subsequently inflammation on a cellular level. Current evidence from research studies provides encouraging data and confirms that this evolving method can potentially have a huge impact on clinical practice as it can be used in the diagnosis and management of very common conditions such as coronary artery disease, ischaemic and non-ischaemic cardiomyopathy, myocarditis and atherosclerosis. Another important emerging concept is that of myocardial energetics. With the use of phosphorus magnetic resonance spectroscopy, myocardial energetic compromise has been proved to be an important feature in the pathophysiological process of several conditions including diabetic cardiomyopathy, inherited cardiomyopathies, valvular heart disease and cardiac transplant rejection. This unique tool is therefore being utilized to assess metabolic alterations in a wide range of cardiovascular diseases. This review systematically examines these state-of-the-art methods in detail and provides an insight into the mechanisms of action and the clinical implications of their use.
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Oral Sucrosomial Iron Is as Effective as Intravenous Ferric Carboxy-Maltose in Treating Anemia in Patients with Ulcerative Colitis.
Bertani, L, Tricò, D, Zanzi, F, Baiano Svizzero, G, Coppini, F, de Bortoli, N, Bellini, M, Antonioli, L, Blandizzi, C, Marchi, S
Nutrients. 2021;(2)
Abstract
Anemia is a frequent complication of ulcerative colitis, and is frequently caused by iron deficiency. Oral iron supplementation displays high rates of gastrointestinal adverse effects. However, the formulation of sucrosomial iron (SI) has shown higher tolerability. We performed a prospective study to compare the effectiveness and tolerability of oral SI and intravenous ferric carboxy-maltose (FCM) in patients with ulcerative colitis in remission and mild-to-moderate anemia. Patients were randomized 1:1 to receive 60 mg/day for 8 weeks and then 30 mg/day for 4 weeks of oral SI or intravenous 1000 mg of FCM at baseline. Hemoglobin and serum levels of iron and ferritin were assessed after 4, 8, and 12 weeks from baseline. Hemoglobin and serum iron increased in both groups after 4 weeks of therapy, and remained stable during follow up, without significant treatment or treatment-by-time interactions (p = 0.25 and p = 0.46 for hemoglobin, respectively; p = 0.25 and p = 0.26 for iron, respectively). Serum ferritin did not increase over time during SI supplementation, while it increased in patients treated with FCM (treatment effect, p = 0.0004; treatment-by-time interaction effect, p = 0.0002). Overall, this study showed that SI and FCM displayed similar effectiveness and tolerability for treatment of mild-to-moderate anemia in patients with ulcerative colitis under remission.
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The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial.
Martens, P, Dupont, M, Dauw, J, Nijst, P, Herbots, L, Dendale, P, Vandervoort, P, Bruckers, L, Tang, WHW, Mullens, W
European heart journal. 2021;(48):4905-4914
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AIMS: Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF. METHODS AND RESULTS Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force-frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (-0.23%, 95% CI -1.44%; +0.97%; P < 0.001). Similarly, LVESV (-9.72 mL, 95% CI -13.5 mL; -5.93 mL vs. -1.83 mL, 95% CI -5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force-frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force-frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM. CONCLUSIONS Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force-frequency relationship.
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Metal-based nanoparticles: Promising tools for the management of cardiovascular diseases.
Younis, NK, Ghoubaira, JA, Bassil, EP, Tantawi, HN, Eid, AH
Nanomedicine : nanotechnology, biology, and medicine. 2021;:102433
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. A search for more effective treatments of CVD is increasingly needed. Major advances in nanotechnology opened new avenues in CVD therapeutics. Owing to their special properties, iron oxide, gold and silver nanoparticles (NPs) could exert various effects in the management and treatment of CVD. The role of iron oxide NPs in the detection and identification of atherosclerotic plaques is receiving increased attention. Moreover, these NPs enhance targeted stem cell delivery, thereby potentiating the regenerative capacity at the injured sites. In addition to their antioxidative and antihypertrophic capacities, gold NPs have also been shown to be useful in the identification of plaques and recognition of inflammatory markers. Contrary to first reports suggestive of their cardio-vasculoprotective role, silver NPs now appear to exert negative effects on the cardiovascular system. Indeed, these NPs appear to negatively modulate inflammation and cholesterol uptake, both of which exacerbate atherosclerosis. Moreover, silver NPs may precipitate bradycardia, conduction block and sudden cardiac death. In this review, we dissect the cellular responses and toxicity profiles of these NPs from various perspectives including cellular and molecular ones.