Iron therapy in heart failure patients without anaemia: possible implications for chronic kidney disease patients.
ABSTRACT: Iron deficiency anaemia is a global health problem that manifests as fatigue and poor physical endurance. Anaemia can be caused by dietary iron deficiency, blood loss or a combination of poor iron absorption and ineffective iron mobilization in patients with chronic disease. Nephrologists caring for patients with impaired renal function understand that iron treatment is necessary to provide adequate iron for erythropoiesis during the treatment of overt anaemia. However, a less well-understood health problem is iron deficiency, which creates symptoms that overlap with those of anaemia and often occurs in concert with chronic disease. Recently, several randomized controlled clinical trials have been conducted to investigate the effects of treatment with intravenous iron in heart failure patients with iron deficiency who may or may not also have anaemia. Given that heart and kidney disease are often comorbid, these clinical trials may have implications for the way nephrologists view their patients with iron deficiency. In this article, we review several clinical studies of intravenous iron therapy for patients with iron deficiency and heart failure and discuss possible implications for the treatment of patients with kidney disease.
Project description:Background:Although anaemia is a common complication of advanced chronic kidney disease (CKD), knowledge of quality of care and management practices in specialist clinics varies. We examined anaemia practices at specialist nephrology clinics within the Irish health system and evaluated the opinions of practicing nephrologists. Methods:A multicentre cross-sectional study was conducted at specialist nephrology clinics across six geographic regions in Ireland. Clinical characteristics and treatment practices were evaluated in a sample of 530 patients with CKD. An accompanying national survey questionnaire captured opinions and treatment strategies of nephrologists on anaemia management. Results:The prevalence of anaemia [defined as haemoglobin (Hb)?<12.0?g/dL] was 37.8%, which increased significantly with advancing CKD (from 21% to 63%; P?<?0.01) and varied across clinical sites (from 36% to 62%; P?<?0.026). Iron deficiency (ID) was present in 46% of all patients tested and 86% of them were not on treatment. More than 45% of anaemic patients were not tested for ID. Respondents differed in their selection of clinical guidelines, threshold targets for erythropoiesis-stimulating agent (ESA) and intravenous iron therapy and anaemia management algorithms were absent in 47% of the clinics. The unexpectedly low rates of ESA use (4.7%) and iron therapy (10.2%) in clinical practice were in contrast to survey responses where 63% of nephrologists indicated ESA therapy initiation when Hb was?<10.0?g/dL and 46% indicated commencement of iron therapy for ferritin?<150?ng/mL. Conclusion:This study highlights substantial variability in the management of anaemia and ID at specialist nephrology clinics with low testing rates for ID, high rates of anaemia and ID and underutilization of effective treatments. Variability in the adoption and implementation of different clinical guidelines was evident.
Project description:Current recommendations for the use of intravenous iron therapy in the management of anaemia in patients with chronic kidney disease (CKD) are based on limited clinical evidence. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anaemia in Chronic Kidney Disease in 2012, a number of randomized clinical trials [notably, the Ferinject Assessment in Patients with Iron Deficiency Anaemia (FIND-CKD) and Randomized Trial to Evaluate IV and Oral Iron in Chronic Kidney Disease (REVOKE) trials] and observational studies have been completed, and a further large clinical trial-Proactive IV Iron Therapy in Dialysis Patients (PIVOTAL)-is currently underway. In this article, the implications of the findings from these recent studies are discussed and the critical evidence gaps that remain to be addressed are highlighted.
Project description:Iron plays a key role in many physiological processes; cells need a very exact quantity of iron. In patients with inflammatory bowel disease, anaemia is a unique example of multifactorial origins, frequently being the result of a combination of iron deficiency and anaemia of chronic disease. The main cause of iron deficiency is the activity of the disease. Therefore, the first aim should be to reach complete clinical remission. The iron supplementation route should be determined according to symptoms, severity of anaemia and taking into account comorbidities and individual risks. Oral iron can only be used in patients with mild anaemia, whose disease is inactive and who have not been previously intolerant to oral iron. Intravenous iron should be the first line treatment in patients with moderate-severe anaemia, in patients with active disease, in patients with poor tolerance to oral iron and when erythropoietin agents or a fast response is needed. Erythropoietin is used in a few patients with anaemia to overcome functional iron deficiency, and blood transfusion is being restricted to refractory cases or acute life-threatening situations.
Project description:In patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency, treatment with intravenous iron has shown a clinical improvement regardless of anaemic status. Cardiac magnetic resonance (CMR) T2* sequence has shown a potential utility for evaluating myocardial iron deficiency. We aimed to evaluate whether T2* sequence significantly changes after ferric carboximaltose (FCM) administration, and if such changes correlate with changes in left ventricle ejection fraction (LVEF).In this pilot study, we included eight patients with chronic symptomatic (New York Heart Association II-III) HFrEF and iron deficiency. A CMR, including T2* analysis, was performed before and at a median of 43?days (interquartile range?=?35-48) after intravenous FCM administration. Pearson or Spearman correlation coefficient (r) was used for bivariate contrast as appropriate. A partial correlation analysis was performed between ?LVEF and ?T2* while controlling for anaemia status at baseline. Anaemia was present in half of patients. After FCM administration, T2* decreased from a median of 39.5 (35.9-48) to 32?ms (32-34.5), P?=?0.012. Simultaneously, a borderline increase in median of LVEF [40% (36-44.5) to 48.5% (38.5-53), P?=?0.091] was registered. In a bivariate correlational analysis, ?T2* was highly correlated with ?LVEF (r?=?-0.747, P?=?0.033). After controlling for anaemia at baseline, the association between ?T2* and ?LVEF persisted [r(partial): -0.865, R2(partial): 0.748, P?=?0.012]. A median regression analysis backed-up these findings.In a small sample of patients with HFrEF and iron deficiency, myocardial iron repletion assessed by CMR was associated to left ventricular remodelling. Further studies are warranted.
Project description:Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups. The prevalence of iron deficiency increases with the severity of heart failure. For a long time, the influence of iron deficiency was underestimated especially in terms of worsening of cardiovascular diseases and of developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and cardiovascular diseases indicated new insights in the improvement of therapy. Experimental studies support the understanding of iron metabolism. Many physicians remain doubtful of the use of intravenous iron due to reports of side effects. The aim of this review is to describe iron metabolism in humans, to highlight the influence of iron deficiency on the course and symptoms of heart failure, discuss diagnostic tools of iron deficiency and provide guidance on the use of intravenous iron.
Project description:Anaemia is a common manifestation in inflammatory bowel disease (IBD) and impairs quality of life. Anaemia in IBD is typically caused by iron deficiency or anaemia of chronic disease. Treatment of iron deficiency with oral iron may lead to gastrointestinal intolerance though this may be related to the dose of iron replacement. New intravenous formulations have emerged which allow safe, rapid and effective correction of iron deficiency in IBD. In this article, we provide a review on the topic and cover recent progress in the field for the practicing gastroenterologist.
Project description:The optimal iron therapy regimen in patients with non-dialysis-dependent chronic kidney disease (CKD) is unknown.Ferinject® assessment in patients with Iron deficiency anaemia and Non-Dialysis-dependent Chronic Kidney Disease (FIND-CKD) was a 56-week, open-label, multicentre, prospective and randomized study of 626 patients with non-dialysis-dependent CKD, anaemia and iron deficiency not receiving erythropoiesis-stimulating agents (ESAs). Patients were randomized (1:1:2) to intravenous (IV) ferric carboxymaltose (FCM), targeting a higher (400-600 µg/L) or lower (100-200 µg/L) ferritin or oral iron therapy. The primary end point was time to initiation of other anaemia management (ESA, other iron therapy or blood transfusion) or haemoglobin (Hb) trigger of two consecutive values <10 g/dL during Weeks 8-52.The primary end point occurred in 36 patients (23.5%), 49 patients (32.2%) and 98 patients (31.8%) in the high-ferritin FCM, low-ferritin FCM and oral iron groups, respectively [hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.44-0.95; P = 0.026 for high-ferritin FCM versus oral iron]. The increase in Hb was greater with high-ferritin FCM versus oral iron (P = 0.014) and a greater proportion of patients achieved an Hb increase ?1 g/dL with high-ferritin FCM versus oral iron (HR: 2.04; 95% CI: 1.52-2.72; P < 0.001). Rates of adverse events and serious adverse events were similar in all groups.Compared with oral iron, IV FCM targeting a ferritin of 400-600 µg/L quickly reached and maintained Hb level, and delayed and/or reduced the need for other anaemia management including ESAs. Within the limitations of this trial, no renal toxicity was observed, with no difference in cardiovascular or infectious events.NCT00994318.
Project description:Iron deficiency is the leading cause of anaemia and is highly prevalent in patients with chronic heart failure (CHF). Iron deficiency, with or without anaemia, can be corrected with intravenous (i.v.) iron therapy. In heart failure patients, iron status screening, diagnosis, and treatment of iron deficiency with ferric carboxymaltose are recommended by the 2016 European Society of Cardiology guidelines, based on results of two randomized controlled trials in CHF patients with iron deficiency. All i.v. iron complexes consist of a polynuclear Fe(III)-oxyhydroxide/oxide core that is stabilized with a compound-specific carbohydrate, which strongly influences their physico-chemical properties (e.g. molecular weight distribution, complex stability, and labile iron content). Thus, the carbohydrate determines the metabolic fate of the complex, affecting its pharmacokinetic/pharmacodynamic profile and interactions with the innate immune system. Accordingly, i.v. iron products belong to the new class of non-biological complex drugs for which regulatory authorities recognized the need for more detailed characterization by orthogonal methods, particularly when assessing generic/follow-on products. Evaluation of published clinical and non-clinical studies with different i.v. iron products in this review suggests that study results obtained with one i.v. iron product should not be assumed to be equivalent to other i.v. iron products that lack comparable study data in CHF. Without head-to-head clinical studies proving the therapeutic equivalence of other i.v. iron products with ferric carboxymaltose, in the highly vulnerable population of heart failure patients, extrapolation of results and substitution with a different i.v. iron product is not recommended.
Project description:Recommendations given for intravenous iron treatment are typically not supported by a high level of evidence. This meta-analysis addressed this by summarising the available date from clinical trials of ferric carboxymaltose using clinical trial reports and published reports.Clinical trial reports were supplemented by electronic literature searches comparing ferric carboxymaltose with active comparators or placebo. Various outcomes were sought for efficacy (attainment of normal haemoglobin (Hb), increase of Hb by a defined amount, for example), together with measures of harm, including serious adverse events and deaths.Fourteen studies were identified with 2,348 randomised patients exposed to ferric carboxymaltose, 832 to oral iron, 762 to placebo, and 384 to intravenous iron sucrose. Additional data were available from cohort studies. Intravenous ferric carboxymaltose was given up to the calculated iron deficit (up to 1,000 mg in one week) for iron deficiency anaemia secondary to chronic kidney disease, blood loss in obstetric and gynaecological conditions, gastrointestinal disease, and other conditions like heart failure. The most common comparator was oral iron, and trials lasted 1 to 24 weeks. Intravenous ferric carboxymaltose improved mean Hb, serum ferritin, and transferrin saturation levels; the mean end-of-trial increase over oral iron was, for Hb 4.8 (95% confidence interval 3.3 to 6.3) g/L, for ferritin 163 (153 to 173) ?g/L, and for transferrin saturation 5.3% (3.7 to 6.8%). Ferric carboxymaltose was significantly better than comparator in achievement of target Hb increase (number needed to treat (NNT) 6.8; 5.3 to 9.7) and target Hb NNT (5.9; 4.7 to 8.1). Serious adverse events and deaths were similar in incidence in ferric carboxymaltose and comparators; rates of constipation, diarrhoea, and nausea or vomiting were lower than with oral iron.This review examined the available trials of intravenous ferric carboxymaltose using details from published papers and unpublished clinical trial reports. It increases the evidence available to support recommendations given for intravenous iron treatment, but there are limited trial data comparing different intravenous iron preparations.
Project description:INTRODUCTION:Preoperative anaemia is linked to poor postsurgical outcome, longer hospital stays, greater risk of complications and mortality. Currently in the UK, some sites have developed anaemia clinics or pathways that use intravenous iron to correct iron deficiency anaemia prior to surgery as their standard of care. Although intravenous iron has been observed to be effective in a variety of patient settings, there is insufficient evidence in its use in cardiac and vascular patients. The aim of this study is to observe the impact and effect of anaemia and its management in patients undergoing cardiac and vascular surgery. In addition, the UK Cardiac and Vascular Surgery Interventional Anaemia Response (CAVIAR) Study is also a feasibility study with the aim to establish anaemia management pathways in the preoperative setting to inform the design of future randomised controlled trials. METHODS AND ANALYSIS:The UK CAVIAR Study is a multicentre, stepped, observational study, in patients awaiting major cardiac or vascular surgery. We will be examining different haematological variables (especially hepcidin), functional capacity and patient outcome. Patients will be compared based on their anaemia status, whether they received intravenous iron in accordance to their hospital's preoperative pathway, and their disease group. The primary outcomes are the change in haemoglobin levels from baseline (before treatment) to before surgery; and the number of successful patients recruited and consented (feasibility). The secondary outcomes will include changes in biomarkers of iron deficiency, length of stay, quality of life and postoperative recovery. ETHICS AND DISSEMINATION:The study protocol was approved by the London-Westminster Research Ethics Committee (15/LO/1569, 27 November 2015). NHS approval was also obtained with each hospital trust. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:Clinical Trials registry (NCT02637102) and the ISRCTN registry (ISRCTN55032357).