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JACC. Heart Failure Jan 2019Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise... (Review)
Review
Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 μg/l, or ferritin, 100 to 300 μg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options.
Topics: Administration, Intravenous; Administration, Oral; Anemia, Iron-Deficiency; Cardiovascular Diseases; Comorbidity; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Ferrous Compounds; Heart Failure; Hematinics; Hemoglobins; Hospitalization; Humans; Maltose; Oxygen Consumption; Prevalence; Quality of Life; Stroke Volume; Transferrin; Walk Test
PubMed: 30553903
DOI: 10.1016/j.jchf.2018.07.015 -
JAMA Feb 2020Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia.
OBJECTIVE
To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose.
DESIGN, SETTING, AND PARTICIPANTS
Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B.
INTERVENTIONS
Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7.
MAIN OUTCOMES AND MEASURES
The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35.
RESULTS
In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117).
CONCLUSIONS AND RELEVANCE
In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.
Topics: Adult; Anemia, Iron-Deficiency; Biomarkers; Disaccharides; Female; Ferric Compounds; Headache; Hematinics; Humans; Hypophosphatemia; Incidence; Male; Maltose; Middle Aged; Nausea; Phosphates
PubMed: 32016310
DOI: 10.1001/jama.2019.22450 -
European Heart Journal Mar 2015The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF). (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF).
METHODS AND RESULTS
CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction ≤45%, elevated natriuretic peptides, and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%). Patients were randomized 1 : 1 to treatment with i.v. iron, as ferric carboxymaltose (FCM, n = 152) or placebo (saline, n = 152) for 52 weeks. The primary end-point was the change in 6-min-walk-test (6MWT) distance from baseline to Week 24. Secondary end-points included changes in New York Heart Association (NYHA) class, Patient Global Assessment (PGA), 6MWT distance, health-related quality of life (QoL), Fatigue Score at Weeks 6, 12, 24, 36, and 52 and the effect of FCM on the rate of hospitalization for worsening HF. Treatment with FCM significantly prolonged 6MWT distance at Week 24 (difference FCM vs. placebo: 33 ± 11 m, P = 0.002). The treatment effect of FCM was consistent in all subgroups and was sustained to Week 52 (difference FCM vs. placebo: 36 ± 11 m, P < 0.001). Throughout the study, an improvement in NYHA class, PGA, QoL, and Fatigue Score in patients treated with FCM was detected with statistical significance observed from Week 24 onwards. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [hazard ratio (95% confidence interval): 0.39 (0.19-0.82), P = 0.009]. The number of deaths (FCM: 12, placebo: 14 deaths) and the incidence of adverse events were comparable between both groups.
CONCLUSION
Treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF (ClinicalTrials.gov number NCT01453608).
Topics: Aged; Cardiotonic Agents; Double-Blind Method; Female; Ferric Compounds; Heart Failure; Hospitalization; Humans; Injections, Intravenous; Iron Deficiencies; Long-Term Care; Male; Maltose; Quality of Life; Treatment Outcome
PubMed: 25176939
DOI: 10.1093/eurheartj/ehu385 -
Methods in Molecular Biology (Clifton,... 2017Although affinity tags are highly effective tools for the expression and purification of recombinant proteins, they generally need to be removed prior to structural and...
Although affinity tags are highly effective tools for the expression and purification of recombinant proteins, they generally need to be removed prior to structural and functional studies. This chapter describes a simple method for overproducing a soluble form of a stable variant of tobacco etch virus (TEV) protease in Escherichia coli and a protocol for purifying it to homogeneity so that it can be used as a reagent for removing affinity tags from recombinant proteins by site-specific endoproteolysis. Further, we cleave a model substrate protein (MBP-NusG) in vitro using the purified TEV protease to illustrate a protease cleavage protocol that can be employed for simple pilot experiments and large-scale protein preparations.
Topics: Chromatography, Affinity; Cloning, Molecular; Endopeptidases; Escherichia coli; Escherichia coli Proteins; Maltose-Binding Proteins; Peptide Elongation Factors; Potyvirus; Proteolysis; Recombinant Fusion Proteins; Solubility; Transcription Factors; Up-Regulation
PubMed: 28470608
DOI: 10.1007/978-1-4939-6887-9_14 -
Archives of Gynecology and Obstetrics Dec 2017Iron deficiency occurs frequently in pregnancy and can be diagnosed by serum ferritin-level measurement (threshold value < 30 μg/L). Screening for iron-deficiency...
Iron deficiency occurs frequently in pregnancy and can be diagnosed by serum ferritin-level measurement (threshold value < 30 μg/L). Screening for iron-deficiency anemia is recommended in every pregnant women, and should be done by serum ferritin-level screening in the first trimester and regular hemoglobin checks at least once per trimester. In the case of iron deficiency with or without anaemia in pregnancy, oral iron therapy should be given as first-line treatment. In the case of severe iron-deficiency anemia, intolerance of oral iron, lack of response to oral iron, or in the case of a clinical need for rapid and efficient treatment of anaemia (e.g., advanced pregnancy), intravenous iron therapy should be administered. In the postpartum period, oral iron therapy should be administered for mild iron-deficiency anemia (haemorrhagic anemia), and intravenous iron therapy for moderately severe-to-severe anemia (Hb < 95 g/L). If there is an indication for intravenous iron therapy in pregnancy or postpartum, iron-containing drugs which have been studied in well-controlled clinical trials in pregnancy and postpartum such as ferric carboxymaltose must be preferred for safety reasons. While anaphylactic reactions are extremely are with non-dextrane products, close surveillance during administration is recommended for all intravenous iron products.
Topics: Administration, Intravenous; Administration, Oral; Anemia, Iron-Deficiency; Female; Ferric Compounds; Ferritins; Humans; Iron; Maltose; Postpartum Period; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Severity of Illness Index; Treatment Outcome
PubMed: 28940095
DOI: 10.1007/s00404-017-4526-2 -
European Journal of Heart Failure Jan 2018Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed... (Meta-Analysis)
Meta-Analysis Review
AIMS
Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID.
METHODS AND RESULTS
Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events.
CONCLUSIONS
Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID.
Topics: Anemia, Iron-Deficiency; Ferric Compounds; Global Health; Heart Failure; Hospitalization; Humans; Iron; Iron Deficiencies; Maltose; Survival Rate
PubMed: 28436136
DOI: 10.1002/ejhf.823 -
ESC Heart Failure Feb 2023Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). The present meta-analysis evaluates the effect of intravenous (IV) iron-carbohydrate... (Meta-Analysis)
Meta-Analysis Review
Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). The present meta-analysis evaluates the effect of intravenous (IV) iron-carbohydrate complex supplementation in patients with HF with reduced ejection fraction (HFrEF) and ID/iron deficiency anaemia (IDA). Randomized controlled trials (RCTs) comparing IV iron-carbohydrate complexes with placebo/standard of care in patients with HFrEF with ID/IDA were identified using Embase (from 1957) and PubMed (from 1989) databases through 25 May 2021. Twelve RCTs including 2381 patients were included in this analysis. The majority (90.8%) of patients receiving IV iron-carbohydrate therapy were administered ferric carboxymaltose (FCM); 7.5% received iron sucrose and 1.6% received iron isomaltoside. IV iron-carbohydrate therapy significantly reduced hospitalization for worsening HF [0.53 (0.42-0.65); P < 0.0001] and first hospitalization for worsening HF or death [0.75 (0.59-0.95); P = 0.016], but did not significantly impact all-cause mortality, compared with control. IV iron-carbohydrate therapy significantly improved functional and exercise capacity compared with the control. There was no significant difference in outcome between IV iron-carbohydrate formulations when similar endpoints were measured. No significant difference in adverse events (AE) was observed between the treatment groups. IV iron-carbohydrate therapy resulted in improvements in a range of clinical outcomes and increased functional and exercise capacity, whereas AEs were not significantly different between IV iron-carbohydrate and placebo/standard of care arms. These findings align with the European Society of Cardiology's 2021 HF guidelines, which recommend the consideration of FCM in symptomatic patients with a left ventricular ejection fraction < 45% and ID.
Topics: Humans; Iron Deficiencies; Hematinics; Anemia, Iron-Deficiency; Iron; Maltose
PubMed: 36178088
DOI: 10.1002/ehf2.14177 -
British Journal of Clinical Pharmacology May 2021Hypophosphataemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to... (Meta-Analysis)
Meta-Analysis Review
AIMS
Hypophosphataemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. The aim of this study was to determine frequency, severity, duration and risk factors of incident hypophosphataemia after treatment with FCM and IIM.
METHODS
A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005-2020 was carried out using the search terms 'ferric carboxymaltose' OR 'iron isomaltoside'. Prospective clinical trials reporting outcomes on hypophosphataemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphataemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphataemia.
RESULTS
Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphataemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 vs. 0.06 mmol/L). Hypophosphataemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphataemia.
CONCLUSION
FCM is associated with a high risk of hypophosphataemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphataemia.
Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Disaccharides; Ferric Compounds; Fibroblast Growth Factor-23; Humans; Hypophosphatemia; Maltose; Prospective Studies
PubMed: 33188534
DOI: 10.1111/bcp.14643 -
Methods in Molecular Biology (Clifton,... 2017Rapid advances in bioengineering and biotechnology over the past three decades have greatly facilitated the production of recombinant proteins in Escherichia coli....
Rapid advances in bioengineering and biotechnology over the past three decades have greatly facilitated the production of recombinant proteins in Escherichia coli. Affinity-based methods that employ protein or peptide based tags for protein purification have been instrumental in this progress. Yet insolubility of recombinant proteins in E. coli remains a persistent problem. One way around this problem is to fuse an aggregation-prone protein to a highly soluble partner. E. coli maltose-binding protein (MBP) is widely acknowledged as a highly effective solubilizing agent. In this chapter, we describe how to construct either a His- or a dual His-MBP tagged fusion protein by Gateway recombinational cloning and how to evaluate their yield and solubility. We also describe a simple and rapid procedure to test the solubility of proteins after removing their N-terminal fusion tags by tobacco etch virus (TEV) protease digestion. The choice of whether to use a His tag or a His-MBP tag can be made on the basis of this solubility test.
Topics: Animals; Base Sequence; Chromatography, Affinity; Cloning, Molecular; Electrophoresis, Polyacrylamide Gel; Endopeptidases; Escherichia coli; Gene Expression; Genetic Vectors; Histidine; Humans; Inclusion Bodies; Maltose-Binding Proteins; Oligopeptides; Recombinant Fusion Proteins; Solubility
PubMed: 28573567
DOI: 10.1007/978-1-4939-7000-1_1 -
Circulation. Heart Failure May 2021Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis....
BACKGROUND
Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited.
METHODS
The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance.
CONCLUSIONS
The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.
Topics: Adolescent; Adult; Aged; Anemia, Iron-Deficiency; Female; Ferric Compounds; Ferritins; Heart Failure; Humans; Male; Maltose; Middle Aged; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left
PubMed: 34003690
DOI: 10.1161/CIRCHEARTFAILURE.120.008100