Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis.

BACKGROUND: Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. METHODS: AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. RESULTS: Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 µg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (Pinteraction=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. CONCLUSIONS: The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02937454.

Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies.

BACKGROUND: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. METHODS: Both studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). RESULTS: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. CONCLUSIONS: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.

Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial.

Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over ≥15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to-severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM.

How important is transfusion avoidance in 2013?

Prior to the advent of recombinant erythropoietin in the late-1980s, blood transfusions were the mainstay of anaemia management in patients with end-stage renal failure, many of whom required "top-up" transfusions every 2 to 4 weeks to relieve the debilitating symptoms of severe anaemia. Erythropoietin therapy, however, allowed for the first time, such patients to achieve a sustained correction of anaemia, and there was a dramatic fall in both the use of red cell transfusions in dialysis units, as well as the associated transfusional iron overload prevalent in dialysis patients. Avoidance of blood transfusions improved access to, and outcomes of, kidney transplantation, due to reduced HLA sensitization. In recent years, however, there have been safety concerns regarding the use of erythropoiesis-stimulating agents (ESAs), and there are signs that the use of blood transfusions is once again increasing. The aim of this review is to reassess how important transfusion avoidance is in 2013, and whether we should still have the same concerns about HLA sensitization that we had 20 years ago.

Exercise therapy in individuals with chronic kidney disease: a systematic review and synthesis of the research evidence.

Chronic kidney disease (CKD) is becoming a serious health problem throughout the world and is one of the most potent known risk factors for cardiovascular disease (CVD) which is considered the leading cause of morbidity and mortality in this cohort of patients. Additional independent risk factors for poor health outcomes among many include diabetes, physical inactivity and physical dysfunction. Physical inactivity partly contributes to the accelerated deterioration of physical function in people in all stages of CKD, to levels that significantly impact on clinically and patient important outcomes such as morbidity, employment, quality of life (QoL) and ultimately survival. Ongoing research aims to determine the effectiveness and impact of exercise rehabilitation on reducing/managing the risk of CVD, alleviating physical function limitations, preventing disability and enhancing QoL. Current research also aims to elucidate the mechanisms via which exercise therapy may contribute to clinically relevant benefits.

Feasibility of randomized controlled trials and long-term implementation of interventions: Insights from a qualitative process evaluation of the PEDAL trial.

Introduction: A multi-site randomized controlled trial was carried out between 2015 and 2019 to evaluate the impacts on quality of life of an intradialytic exercise programme for people living with chronic kidney disease. This included a qualitative process evaluation which gave valuable insights in relation to feasibility of the trial and of the intervention in the long-term. These can inform future clinical Trial design and evaluation studies. Methods: A constructivist phenomenological approach underpinned face-to-face, semi-structured interviews. Purposive recruitment ensured inclusion of participants in different arms of the PEDAL Trial, providers with different roles and trial team members from seven Renal Units in five study regions. Following ethical review, those willing took part in one interview in the Renal Unit. Audio-recorded interviews were transcribed (intelligent verbatim) and inductively thematically analyzed. Results: Participants (n = 65) (Intervention arm: 26% completed; 13% who did not; Usual care arm: 13%; 46% women; 54% men; mean age 60 year) and providers (n = 39) were interviewed (23% PEDAL Trial team members). Three themes emerged: (1) Implementing the Intervention; (2) Implementing the trial; and (3) Engagement of the clinical team. Explanatory theory named "the Ideal Scenario" was developed, illustrating complex interactions between different aspects of intervention and trial implementation with the clinical context. This describes characteristics likely to optimize trial feasibility and intervention sustainability in the long-term. Key aspects of this relate to careful integration of the trial within the clinical context to optimize promotion of the trial in the short-term and engagement and ownership in the long-term. Strong leadership in both the clinical and trial teams is crucial to ensure a proactive and empowering culture. Conclusion: Novel explanatory theory is proposed with relevance for Implementation Science. The "Ideal Scenario" is provided to guide trialists in pre-emptive and ongoing risk analysis relating to trial feasibility and long-term intervention implementation. Alternative study designs should be explored to minimize the research-to-practice gap and optimize the likelihood of informative findings and long-term implementation. These might include Realist Randomized Controlled Trials and Hybrid Effectiveness-Implementation studies.

Step-Wise Management of Anemia in Patients With Chronic Kidney Disease in Primary Care: Qualitative Study.

INTRODUCTION: Anemia is common in chronic kidney disease (CKD) and is associated with increased cardiovascular risk and reduced quality of life, but is often sub-optimally managed. Most patients are managed in primary care alongside other comorbidities. Interventions to improve the management of anemia in CKD in this setting are needed. METHODS: We conducted a qualitative study to evaluate how an audit-based education (ABE) intervention might improve the management of anemia in CKD. We explored outcomes that would be relevant to practitioners and patients, that exposed variation of practice from National Institute for Health and Care Excellence (NICE) guidelines, and whether the intervention was feasible and acceptable. RESULTS: Practitioners (n = 5 groups) and patients (n = 7) from 4 London general practices participated in discussions. Practitioners welcomed the evidence-based step-wise intervention. However, prescribing erythropoiesis-stimulating agents (ESAs) was felt to be outside of their scope of practice. There was a gap between NICE guidance and clinical practice in primary care. Iron studies were not well understood and anemia management was often conservative or delayed. Patients were often unaware of having CKD, and were more concerned about their other comorbidities, but largely trusted their GPs to manage them appropriately. CONCLUSIONS: The first steps of the intervention were welcomed by practitioners, but they expressed concerns about independently prescribing ESAs. Renal physicians and GPs could develop shared care protocols for ESA use in primary care. There is scope to improve awareness of renal anemia, and enhance knowledge of guideline recommendations; and our intervention should be modified accordingly.

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.

Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial.

BACKGROUND: Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly. METHODS: Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11-13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50-53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953. RESULTS: Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups. CONCLUSIONS: Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

Iron Sucrose: A Wealth of Experience in Treating Iron Deficiency.

Iron deficiency and iron-deficiency anemia are associated with increased morbidity and mortality in a wide range of conditions. In many patient populations, this can be treated effectively with oral iron supplementation; but in patients who are unable to take or who do not respond to oral iron therapy, intravenous iron administration is recommended. Furthermore, in certain conditions, such as end-stage kidney disease, chronic heart failure, and inflammatory bowel disease, intravenous iron administration has become first-line treatment. One of the first available intravenous iron preparations is iron sucrose (Venofer®), a nanomedicine that has been used clinically since 1949. Treatment with iron sucrose is particularly beneficial owing to its ability to rapidly increase hemoglobin, ferritin, and transferrin saturation levels, with an acceptable safety profile. Recently, important new data relating to the use of iron sucrose, including the findings from the landmark PIVOTAL trial in patients with end-stage kidney disease, have been reported. Several years ago, a number of iron sucrose similars became available, although there have been concerns about the clinical appropriateness of substituting the original iron sucrose with an iron sucrose similar because of differences in efficacy and safety. This is a result of the complex and unique physicochemical properties of nanomedicines such as iron sucrose, which make copying the molecule difficult and problematic. In this review, we summarize the evidence accumulated during 70 years of clinical experience with iron sucrose in terms of efficacy, safety, and cost-effectiveness.

Intra-dialytic exercise training: a pragmatic approach.

UNLABELLED: This continuing education paper outlines the skills and knowledge required to plan, implement and evaluate a pragmatic approach to intra-dialytic exercise training. AIM: The aim of this continuing education article is to enable the nephrology multi-disciplinary team (MDT) to plan, implement and evaluate the provision of intra-dialytic exercise training for patients receiving haemodialysis therapy. LEARNING OUTCOMES: After reading this article the reader should be able to: Appreciate the level of evidence base for the clinical effectiveness of renal exercise rehabilitation and locate credible sources of research and educational information Understand and consider the need for appropriate evaluation and assessment outcomes as part of a renal rehabilitation plan Understand the components of exercise programming and prescription as part of an integrated renal rehabilitation plan Develop a sustainable longer term exercise and physical activity plan.

Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches.

Anemia and iron deficiency are common in patients with heart failure (HF), and are associated with worse symptoms and adverse outcomes in this population. Although the two can occur together, anemia in HF is often not caused by iron deficiency, and iron deficiency can be present without causing anemia. Erythropoiesis-stimulating agents have been investigated extensively in the past few years and might be of benefit in patients with HF and anemia. However, concerns have arisen regarding the safety of erythropoiesis-stimulating agents in patients with chronic kidney disease and so the results of a large mortality trial are eagerly awaited to provide information on safety in patients with HF. Iron supplementation or replacement is a much older treatment option for patients with HF and anemia, but questions about the safety of intravenous iron, and absorption problems with oral formulations have prevented its widespread use to date. In the past few years, however, new data on the importance of iron deficiency in HF have become available, and a number of studies with intravenous iron have shown promising results. Therefore, this treatment approach is likely to become an attractive option for patients with HF and iron deficiency, both with and without anemia.

Iron supplementation in the non-dialysis chronic kidney disease (ND-CKD) patient: oral or intravenous?

BACKGROUND: The management of iron-deficiency anaemia in patients with non-dialysis chronic kidney disease (ND-CKD) remains controversial, particularly regarding the use of oral versus intravenous iron supplementation. METHODS: A PubMed search from 1970 to February 2009 was conducted to identify relevant research articles. FINDINGS: Iron supplementation is advisable for all iron-deficient CKD patients receiving erythropoiesis stimulating agents (ESAs), and intravenous iron may be preferable to oral iron. However, there is also a growing body of data indicating that iron supplementation may avoid or delay the need for ESA therapy in some ND-CKD patients. In each of four randomised trials that included ND-CKD patients without ESA, the haemoglobin response was greater with i.v. versus oral iron. Moreover, some ND-CKD patients who remain anaemic on oral iron may subsequently respond to i.v. iron. Newer preparations (ferric carboxymaltose and ferumoxytol) permit rapid, high-dose administration. In a randomised study, a single 15-minute injection of ferric carboxymaltose, with up to two additional doses as required, resulted in 53.2% of ND-CKD patients achieving > or =1 g/dL increase in haemoglobin by day 56 without ESA, compared to 29.9% of patients given oral iron supplements. Two large, randomised, ongoing trials will address the important question of whether i.v. or oral iron supplementation affects the progression of renal dysfunction. While i.v. iron is more costly than oral iron, the cost differential over time may be lower than widely believed, and i.v. therapy avoids the poor absorption, gastrointestinal intolerance and non-compliance associated with oral preparations. In terms of safety, true anaphylaxis does not occur with modern preparations such as iron sucrose and iron gluconate. The novel preparations ferric carboxymaltose and ferumoxytol do not require a test dose and appear to offer a good safety profile, but long-term safety monitoring is mandatory. CONCLUSIONS: Intravenous iron offers an effective, feasible route towards reducing the heavy burden of iron-deficiency anaemia in the non-dialysis CKD patient, even in the absence of ESA therapy.