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Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100–299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62–1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64–1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70–1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58–0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66–0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47–0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. Vifor Pharma.

Abstract Study Objectives Iron therapy is associated with improvements in restless legs syndrome (RLS). This multicenter, randomized, double-blind study evaluated the effect of intravenous ferric carboxymaltose (FCM) on RLS. Methods A total of 209 adult patients with a baseline International RLS (IRLS) score ≥ 15 were randomized (1:1) to FCM (750 mg/15 mL) or placebo on study days 0 and 5. Ongoing RLS medication was tapered starting on Day 5, with the goal of discontinuing treatment or achieving the lowest effective dose. Co-primary efficacy endpoints were changed from baseline in IRLS total score and the proportion of patients rated as much/very much improved on the Clinical Global Impression (CGI)–investigator (CGI-I) scale at day 42 in the “As-Treated” population. Results The “As-Treated” population comprised 107 FCM and 101 placebo recipients; 88 (82.2%) and 68 (67.3%), respectively, completed the day 42 assessment. The IRLS score reduction was significantly greater with FCM versus placebo: least-squares mean (95% confidence interval [CI]) −8.0 (−9.5, −6.4) versus −4.8 (−6.4, −3.1); p = .0036. No significant difference was observed in the proportion of FCM (35.5%) and placebo (28.7%) recipients with a CGI-I response (odds ratio 1.37 [95% CI: 0.76, 2.47]; p = .2987). Fewer patients treated with FCM (32.7%) than placebo (59.4%) received RLS interventions between day 5 and study end (p = .0002). FCM was well tolerated. Conclusions The IRLS score improved with intravenous FCM versus placebo, although the combination of both co-primary endpoints was not met. Potential methodological problems in the study design are discussed. Graphical Abstract Graphical Abstract

Over 46% of African pregnant women are anemic. Oral iron is recommended but often suboptimal, particularly late in pregnancy. Intravenous ferric carboxymaltose (FCM) could treat anemia in women in the third trimester in sub-Saharan Africa. In an open-label, individually randomized trial in antenatal clinics in southern Malawi, we randomized 590 women at 27–35 weeks of gestation with capillary hemoglobin <10.0 g dl −1 to FCM (20 mg kg −1 up to 1,000 mg, once at enrollment) or standard of care (60 mg elemental iron, twice daily for 90 days). Participants and their infants were followed to 4 weeks postpartum. Primary outcomes were maternal anemia at 36 weeks’ gestation or delivery (whichever occurred first) and neonatal birthweight. At the primary timepoint, 126 of 270 (46.7%) of women in the FCM group were anemic, compared to 170 of 271 (67.3%) women in the standard-of-care group (PR, 0.74 (95% CI 0.64, 0.87); P  = 0.0002). There was no difference between groups in birthweight (mean difference 10.9 g (−65.7, 87.5 g); P  = 0.78). No serious infusion-related reactions occurred, and there were no differences in adverse events between groups. In Malawian women in late pregnancy, FCM effectively and safely reduced anemia before childbirth. Australia New Zealand Clinical Trial registration: ANZCTR12621001239853 A randomized controlled trial in the third trimester of pregnancy in Malawian women with anemia found a single dose of intravenous ferric carboxymaltose to be more effective than standard of care (that is, twice-daily oral iron) in reducing anemia rates before childbirth.

INTRODUCTION:Limited evidence exists on the optimal strategy to correct iron deficiency anemia after variceal bleeding (VB) in cirrhosis. This trial compared the efficacy and safety of intravenous ferric carboxymaltose (IV-FCM) with those of oral iron therapy in this cohort.METHODS:In this open-label, single-center, randomized controlled trial, eligible patients with hemoglobin <10 g/dL and iron deficiency (ferritin <100 ng/mL) after VB received either IV-FCM (1,500-2,000 mg) divided into 2 doses (n = 48) or oral carbonyl iron (100 mg elemental iron/day) (n = 44) for 3 months. The primary outcome was change in hemoglobin at 3 months. Secondary outcomes included improvement in anemia (last hemoglobin >12 g/dL), normalization of iron stores (ferritin >100 ng/mL), liver-related adverse events, adverse drug reactions, and changes in quality of life (CLDQOL questionnaire).RESULTS:Baseline characteristics, including median Child-Turcotte-Pugh score 7 (interquartile range [IQR] 6-9), Model for End-Stage Liver Disease score 12 (IQR 10-17), blood hemoglobin (8.25 ± 1.06 g/dL), and ferritin (30.00 ng/mL [15.00-66.50]), were comparable in both arms. The median increase in hemoglobin at 3 months in the IV and oral arms was 3.65 g/dL (IQR 2.55-5.25) and 1.10 g/dL (IQR 0.05-2.90 g/dL) (P < 0.001), respectively. Iron stores normalized in 84.6% and 21% of the IV and oral arms, respectively (P < 0.001). Anemia improved in 50% and 21.9% in the IV and oral arms, respectively (P < 0.009). Patients in the IV arm showed a significant improvement in all domains of CLDQOL. Liver-related adverse events were comparable in both arms. Transient mild/moderate hypophosphatemia developed in 43% of patients receiving IV-FCM.DISCUSSION:Intravenous iron replacement is efficacious and safe to treat iron deficiency anemia after VB in patients with cirrhosis.

Ferric carboxymaltose (FCM) is widely used to correct anemia and replenish iron stores rapidly, particularly in Western populations. However, lower doses of FCM are typically used in East Asia, with limited research on their effectiveness, especially in postpartum women. This randomized controlled trial aimed to assess the efficacy of low-dose FCM compared with oral ferrous sulfate in increasing postpartum hemoglobin (Hb) levels and replenishing iron stores in East Asian women. Sixty postpartum women with Hb levels < 10 g/dL and serum ferritin ≤ 30 ng/mL were randomized to receive either intravenous FCM (500 mg at baseline and 2 weeks) or oral ferrous sulfate (210 mg daily for 4 weeks). The primary outcome was the increase in Hb levels at 2 weeks post-enrollment. Secondary outcomes included serum ferritin, transferrin saturation, the Edinburgh Postnatal Depression Scale (EPDS) score, and adverse events at 4 weeks. The FCM group demonstrated a significantly greater increase in Hb levels at 2 weeks (mean difference 0.42 g/dL; 95% CI: 0.12–0.72; P =  0.006), with markedly higher ferritin (adjusted mean difference 356.0 ng/mL; 95% CI: 321.0–403.0; P <  0.001) and transferrin saturation (adjusted mean difference 10.76%; 95% CI: 4.20–17.31; P =  0.002) at 4 weeks. Although there was no significant difference in final Hb levels at 4 weeks (mean difference 0.36 g/dL; 95% CI: -0.01–0.72; P =  0.055), the FCM group had a lower median EPDS score (median difference -3.0; 95% CI: -5.0 to -1.0; P =  0.002) and fewer gastrointestinal side effects, including constipation and nausea. Hypophosphatemia occurred asymptomatically in three patients in the FCM group. These findings suggest that low-dose FCM infusion is highly effective in increasing Hb levels at 2 weeks post-enrollment, with fewer gastrointestinal side effects and higher ferritin levels observed at 4 weeks post-enrollment compared with oral ferrous sulfate. This study was registered at the UMIN Clinical Trials Registry, which meets the requirements of the ICMJE, on December 1, 2021 (ID: UMIN000046049).

Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue. Fatigued women (Piper Fatigue Scale [PFS] score ≥5) with iron deficiency (ferritin <50 µg/L and transferrin saturation <20%, or ferritin <15 µg/L) and normal or borderline hemoglobin (≥115 g/L) were enrolled in 21 sites in Austria, Germany, Sweden and Switzerland, blinded to the study drug and randomized (computer-generated randomization sequence) to a single FCM (1000 mg iron) or saline (placebo) infusion. Primary endpoint was the proportion of patients with reduced fatigue (≥1 point decrease in PFS score from baseline to Day 56). The full analysis included 290 women (FCM 144, placebo 146). Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68, 95%CI 1.05-2.70; p = 0.03). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients (p<0.001). At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM. 'Power of attention' improved better in FCM-treated patients with ferritin <15 µg/L. Treatment-emergent adverse events (placebo 114, FCM 209; most frequently headache, nasopharyngitis, pyrexia and nausea) were mainly mild or moderate. A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women's health, and a normal iron status should be maintained independent of hemoglobin levels. ClinicalTrials.gov NCT01110356.

In patients with heart failure and iron deficiency, intravenous iron therapy improved functional capacity and the quality of life. The benefit was similar in patients with anemia and those without anemia. Iron therapy may have a role in treating heart failure when iron deficiency is also present. In patients with heart failure and iron deficiency, intravenous iron therapy improved functional capacity and the quality of life. Iron therapy may have a role in treating heart failure when iron deficiency is also present. Recent developments in the management of chronic heart failure in patients with an impaired left ventricular ejection fraction have changed the natural history of this clinical syndrome and improved patients' outcomes. 1 , 2 However, the normal daily activities of many patients with heart failure remain restricted; they report symptoms of fatigue and dyspnea that adversely affect their quality of life, leading to high morbidity. 3 , 4 Therapeutic options to improve functional capacity in patients with heart failure are limited, and novel therapies are needed. Numerous mechanisms unrelated to hemodynamic dysfunction may underlie impaired exercise tolerance in patients with chronic heart failure. Among . . .

Iron deficiency anemia in the perioperative setting is treated predominantly with intravenous iron formulation, of which ferric carboxymaltose may induce hypophosphatemia by modulating fibroblast growth factor 23. In this single-center, prospective, randomized, double-blind trial, we consented 92 adult patients scheduled for elective major abdominal or thoracic surgery. These patients either had isolated iron deficiency (plasma ferritin <100 ng/mL or transferrin saturation < 20 %) or iron deficiency anemia (hemoglobin (Hb) 100–130 g/L with plasma ferritin <100 ng/mL or transferrin saturation < 20 %). Preoperatively, participants received a single preoperative intravenous dose of ferric carboxymaltose and were then randomly assigned to receive either phosphate or placebo, administered orally three times a day for 30 days corresponding to an 18 mmol dose of daily phosphate supplementation in the intervention group. The primary endpoint was the minimum serum phosphate concentration during follow-up visits. The key secondary efficacy endpoint was mean perioperative hemoglobin concentration of postoperative days 0, 2 and 4, assessing the non-inferiority of additional phosphate supplementation. We randomly consented 46 patients in each group (mean ± SD age 56 ± 17 years, 57 % female). Minimal phosphate concentration was 0.49 ± 0.21 mmol/L in the treatment group and 0.42 ± 0.17 mmol/L in the placebo group (p = 0.12, two-sided p-value). Average mean hemoglobin was 110 ± 16 g/L in the treatment and 113 ± 13 g/L in the placebo group (p = 0.023, one-sided p-value for non-inferiority). Hypophosphatemia occurred in 32 patients (70 %) of the treatment group and in 39 patients (85 %) of the placebo group (odds ratio 0.15, 95 % CI from 0.02 to 0.77, p = 0.014). Secondary outcomes, such as rescue medication use, core muscle strength and MOCA test scores, did not differ between groups. Co-administration of oral phosphate supplementation to ferric carboxymaltose cannot prevent hypophosphatemia. However, hypophosphatemia occurs in fewer patients. Phosphate co-administration did not impede the treatment of iron deficiency anemia with ferric carboxymaltose. •Ferric carboxymaltose may induce fibroblast growth factor 23 mediated hypophosphatemia.•We evaluated the effect of oral phosphate supplementation on mitigating hypophosphatemia caused by ferric carboxymaltose.•Oral phosphate supplementation cannot prevent hypophosphatemia but, hypophosphatemia occurs in fewer patients.

Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0–3) to zero units in the treatment group (0–2, during the first 7 days (odds ratio 0·70 [95% CI 0·50–0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0–2]) versus the placebo group (1 [0–3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. Vifor Pharma and Swiss Foundation for Anaesthesia Research.

Abstract Background Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. Methods In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center’s standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. Results For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. Conclusions Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated. Graphical Abstract Graphical Abstract