title: Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency† Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial Ferric carboxymaltose in patients with heart failure and iron deficiency. Single‐dose intravenous iron in Southeast Asian heart failure patients: A pilot randomized placebo‐controlled study (PRACTICE‐ASIA‐HF) Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials Four Weeks of IV Iron Supplementation Reduces Perceived Fatigue and Mood Disturbance in Distance Runners Intravenous iron isomaltoside improves hemoglobin concentration and iron stores in female iron‐deficient blood donors: a randomized double‐blind placebo‐controlled clinical trial The Important Role for Intravenous Iron in Perioperative Patient Blood Management in Major Abdominal Surgery Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Evaluation of a Single Dose of Ferric Carboxymaltose in Fatigued, Iron-Deficient Women – PREFER a Randomized, Placebo-Controlled Study Iron Deficiency Generates Secondary Thrombocytosis and Platelet Activation in IBD: the Randomized, Controlled ThromboVIT Trial Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease Efficacy of Intravenous Iron Sucrose in Hemodialysis Patients with Restless Legs Syndrome (RLS): A Randomized, Placebo-Controlled Study Comparison of short-term efficacy of iron sucrose with those of ferric chloride in hemodialysis patients: An open-label study The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial) A randomized trial of iron deficiency testing strategies in hemodialysis patients. Randomized double-blind safety comparison of intravenous iron dextran versus iron sucrose in an adult non-hemodialysis outpatient population: A feasibility study Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Non-anaemic iron deficiency impairs response to pulmonary rehabilitation in COPD. Sodium ferric gluconate (SFG) in complex with sucrose for IV infusion: bioequivalence of a new generic product with the branded product in healthy volunteers Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial Effect of iron injections on aerobic-exercise performance of iron-depleted female athletes. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. A Blinded, Randomized, Placebo-Controlled Study to Investigate the Efficacy and Safety of Ferric Carboxymaltose in Iron-Deficient Patients with Fibromyalgia EFFECTS OF MODEST IRON LOADING ON IRON INDICES IN HEALTHY INDIVIDUALS. Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency. Associations between non-anaemic iron deficiency and outcomes following surgery for colorectal cancer: An exploratory study of outcomes relevant to prospective observational studies Iron deficiency is associated with higher mortality in patients undergoing cardiac surgery: a prospective study. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency
abstract: 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 r and omized 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 result ed in sustainable improvement in functional capacity , symptoms , and QoL and may be associated with risk reduction of hospitalization for worsening HF ( Clinical Trials.gov number NCT01453608 ) Aims Therapy with i.v . iron in patients with chronic heart failure ( CHF ) and iron deficiency ( ID ) improves symptoms , functional capacity , and quality of life . We sought to investigate whether these beneficial outcomes are independent of anaemia . Methods and results FAIR-HF r and omized 459 patients with CHF [ NYHA class II or III , LVEF ≤40 % ( NYHA II ) or ≤45 % ( NYHA III ) ] and ID to i.v . iron as ferric carboxymaltose ( FCM ) or placebo in a 2:1 ratio . We analysed the efficacy and safety according to the presence or absence of anaemia ( haemoglobin ≤120 g/L ) at baseline . Of 459 patients , 232 had anaemia at baseline ( 51 % ) . The effect of FCM on the primary endpoints of self-reported Patient Global Assessment ( PGA ) and NYHA class at week 24 was similar in patients with and without anaemia [ odds ratio ( OR ) for improvement , 2.48 vs. 2.60 , P = 0.97 for PGA and 1.90 vs. 3.39 , P = 0.51 for NYHA ) . Results were also similar for the secondary endpoints , including PGA and NYHA at weeks 4 and 12 , 6 min walk test distance , Kansas City Cardiomyopathy Question naire overall score , and European Quality of Life-5 Dimensions Visual Analogue Scale at most time points . Regarding safety , no differences were noticed in the rates of death or first hospitalization  between FCM and placebo both in anaemic and in non-anaemic patients . Conclusions Treatment of ID with FCM in patients with CHF is equally efficacious and shows a similar favourable safety profile irrespective of anaemia . Iron status should be assessed in symptomatic CHF patients both with and without anaemia and treatment of ID should be considered BACKGROUND Iron deficiency may impair aerobic performance . This study aim ed to determine whether treatment with intravenous iron ( ferric carboxymaltose ) would improve symptoms in patients who had heart failure , reduced left ventricular ejection fraction , and iron deficiency , either with or without anemia . METHODS We enrolled 459 patients with chronic heart failure of New York Heart Association ( NYHA ) functional class II or III , a left ventricular ejection fraction of 40 % or less ( for patients with NYHA class II ) or 45 % or less ( for NYHA class III ) , iron deficiency ( ferritin level < 100 microg per liter or between 100 and 299 microg per liter , if the transferrin saturation was < 20 % ) , and a hemoglobin level of 95 to 135 g per liter . Patients were r and omly assigned , in a 2:1 ratio , to receive 200 mg of intravenous iron ( ferric carboxymaltose ) or saline ( placebo ) . The primary end points were the self-reported Patient Global Assessment and NYHA functional class , both at week 24 . Secondary end points included the distance walked in 6 minutes and the health-related quality of life . RESULTS Among the patients receiving ferric carboxymaltose , 50 % reported being much or moderately improved , as compared with 28 % of patients receiving placebo , according to the Patient Global Assessment ( odds ratio for improvement , 2.51 ; 95 % confidence interval [ CI ] , 1.75 to 3.61 ) . Among the patients assigned to ferric carboxymaltose , 47 % had an NYHA functional class I or II at week 24 , as compared with 30 % of patients assigned to placebo ( odds ratio for improvement by one class , 2.40 ; 95 % CI , 1.55 to 3.71 ) . Results were similar in patients with anemia and those without anemia . Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality -of-life assessment s. The rates of death , adverse events , and serious adverse events were similar in the two study groups . CONCLUSIONS Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency , with or without anemia , improves symptoms , functional capacity , and quality of life ; the side-effect profile is acceptable . ( Clinical Trials.gov number , NCT00520780 ) Abstract Aims Iron deficiency is highly prevalent in Southeast Asians with heart failure ( HF ) and associated with worse outcomes . This trial aim ed to assess the effect of intravenous iron in Southeast Asians hospitalized with decompensated HF . Methods and results Fifty patients hospitalized for acute decompensated HF , regardless of ejection fraction , with iron deficiency ( defined as serum ferritin < 300 ng/mL if transferrin saturation is < 20 % ) were r and omized to receive either one dose of intravenous ferric carboxymaltose ( FCM ) 1000 mg or placebo ( 0.9 % saline ) following HF stabilization and before discharge in two Singapore tertiary centres . The primary endpoint was difference in 6‐min walk test ( 6MWT ) distance over 12 weeks , while secondary endpoints were quality of life assessed using vali date d Kansas City Cardiomyopathy Question naire ( KCCQ ) and Visual Analogue Scale ( VAS ) . Improvement in 6MWT distance at Week 12 was observed in both FCM and placebo groups ( from 252 ± 123 to 334 ± 128 m and from 243 ± 67 to 301 ± 83 m , respectively ) . Unadjusted analysis showed 6MWT distance for FCM exceeded that for placebo , but adjustment for baseline covariates and time attenuated this effect { adjusted mean difference between groups : 0.88 m [ 95 % confidence interval ( CI ) −30.2 to 32.0 , P = 0.956]}. KCCQ overall summary and VAS were similar in both groups [ adjusted mean difference : KCCQ −1.48 ( 95 % CI −8.27 to 5.31 , P = 0.670 ) and VAS 0.26 ( 95 % CI −0.33 to 0.86 , P =  0.386  ) ] . FCM  was well tolerated with no serious treatment‐related adverse events . Conclusions Intravenous FCM administered pre‐discharge in Southeast Asians hospitalized with decompensated HF is clinical ly feasible . Changes in 6MWT distance should be measured beyond Week 12 to account for background therapy effects Objective Iron supplementation in iron-deficiency anaemia is st and ard practice , but the benefits of iron supplementation in iron-deficient non-anaemic ( IDNA ) individuals remains controversial . Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults . Design Systematic review and meta- analysis of r and omised controlled trials ( RCTs ) . Setting Primary care . Participants Adults ( ≥18 years ) who were iron deficient but non-anaemic . Interventions Oral , intramuscular or intravenous iron supplementation ; all therapy doses , frequencies and duration s were included . Comparators Placebo or active therapy . Results We identified RCTs in Medline , Embase , Cochrane Central Register of Controlled Trials , Cumulative Index of Nursing and Allied Health , SportD iscus and CAB Abstract s from inception to 31 October 2016 . We search ed the WHO ’s International Clinical Trials Registry Platform for relevant ongoing trials and performed forward search es of included trials and relevant review s in Web of Science . We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment , Development and Evaluation methodology . From 11 580 citations , we included 18 unique trials and 2 companion papers enrolling 1170 patients . Using a Mantel-Haenszel r and om-effects model , iron supplementation was associated with reduced self-reported fatigue ( st and ardised mean difference ( SMD ) −0.38 ; 95 % CI −0.52 to −0.23 ; I2 0 % ; 4 trials ; 714 participants ) but was not associated with differences in objective measures of physical capacity , including maximal oxygen consumption ( SMD 0.11 ; 95 % CI −0.15 to 0.37 ; I2 0 % ; 9 trials ; 235 participants ) and timed methods of exercise testing  . Iron supplementation significantly increased serum haemoglobin concentration ( MD 4.01 g/L ; 95 % CI 1.22 to 6.81 ; I2 48 % ; 12 trials ; 298 participants ) and serum ferritin ( MD 9.23 µmol/L ; 95 % CI 6.48 to 11.97 ; I2 58 % ; 14 trials ; 616 participants ) . Conclusion In IDNA adults , iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity . Given the global prevalence of both iron deficiency and fatigue , patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia . PROSPERO registration number CRD42014007085 Purpose To determine the effect of intravenous iron supplementation on performance , fatigue and overall mood in runners without clinical iron deficiency . Methods Fourteen distance runners with serum ferritin 30–100 µg·L−1 were r and omly assigned to receive three blinded injections of intravenous ferric-carboxymaltose ( 2 ml , 100 mg , IRON ) or normal saline ( PLACEBO ) over four weeks ( weeks 0 , 2 , 4 ) . Athletes performed a 3,000 m time trial and 10 × 400 m monitored training session on consecutive days at week 0 and again following each injection . Hemoglobin mass ( Hbmass ) was assessed via carbon monoxide rebreathing at weeks 0 and 6 . Fatigue and mood were determined bi-weekly until week 6 via Total Fatigue Score ( TFS ) and Total Mood Disturbance ( TMD ) using the Brief Fatigue Inventory and Brunel Mood Scale . Data were analyzed using magnitude-based inferences , based on the unequal variances t-statistic and Cohen 's Effect sizes ( ES ) . Results Serum ferritin increased in IRON only ( Week 0 : 62.8±21.9 , Week 4 : 128.1±46.6 µg·L−1 ; p = 0.002 ) and remained elevated two weeks after the final injection ( 127.0±66.3 µg·L−1 , p = 0.01 ) , without significant changes in Hbmass . Supplementation had a moderate effect on TMD of IRON ( ES -0.77 ) with scores at week 6 lower than PLACEBO ( ES -1.58 , p = 0.02 ) . Similarly , at week 6 , TFS was significantly improved in IRON vs. PLACEBO ( ES –1.54 , p = 0.05 ) . There were no significant improvements in 3,000 m time in either group ( Week 0 vs. Week 4 ; Iron : 625.6±55.5 s vs. 625.4±52.7 s ; PLACEBO : 624.8±47.2 s vs. 639.1±59.7 s ) ; but IRON reduced their average time for the 10 × 400 m training session at week 2 ( Week 0 : 78.0±6.6 s , Week 2 : 77.2±6.3 ; ES–0.20 , p = 0.004 ) . Conclusion During 6 weeks of training , intravenous iron supplementation improved perceived fatigue and mood of trained athletes with no clinical iron deficiency , without concurrent improvements in oxygen transport capacity or performance BACKGROUND This trial evaluated the efficacy and safety of intravenous ( IV ) iron isomaltoside ( Monofer ) in comparison with placebo in first-time female blood donors . STUDY DESIGN AND METHODS The trial was a prospect i ve , double blind , placebo-controlled , r and omized , comparative , single-center trial of 85 first-time female blood donors . The subjects were r and omly assigned 1:1 to either 1000 mg IV iron isomaltoside infusion or placebo . The primary endpoint of the trial was change in hemoglobin ( Hb ) from baseline to right before the third blood donation . RESULTS The increase in Hb was significantly higher for iron isomaltoside compared with placebo right before both the second blood donation ( p = 0.0327 ) and the third blood donation ( primary endpoint , p < 0.0001 ) . Improvements in other iron-related variables ( plasma iron , plasma ferritin , transferrin saturation , and reticulocyte count ) in favor of iron isomaltoside were also observed . The trial was not powered on patient-reported outcomes . However , improvements in iron stores and Hb levels after iron isomaltoside administration were supported by the fact that several of the fatigue symptoms scores showed numerical differences in favor of iron isomaltoside . There were no differences in side effects between the groups . CONCLUSION In iron-deficient female blood donors a single IV iron isomaltoside administration result ed in an improvement in Hb concentration and iron stores and demonstrated a favorable safety profile comparable to placebo Objective : To determine if preoperative intravenous ( IV ) iron improves outcomes in abdominal surgery patients . Summary Background Data : Preoperative iron deficiency anemia ( IDA ) occurs frequently ; however if left untreated , increases the risk of blood transfusion allogeneic blood transfusion ( ABT ) . Limited evidence supports IDA treatment with preoperative IV iron . This r and omized controlled trial aim ed to determine whether perioperative IV iron reduced the need for ABT . Methods : Between August 2011 and November 2014 , 72 patients with IDA were assigned to receive either IV iron or usual care . The primary endpoint was incidence of ABT . Secondary endpoints were various hemoglobin ( Hb ) levels , change in Hb between time points , length of stay , iron status , morbidity , mortality , and quality of life 4 weeks postsurgery . Results : A 60 % reduction in ABT was observed in the IV iron group compared with the usual care group ( 31.25 % vs 12.5 % ) . Hb values , although similar at r and omization , improved by 0.8 g/dL with IV iron compared with 0.1 g/dL with usual care ( P = 0.01 ) by the day of admission . The IV iron group had higher Hb 4 weeks after discharge compared with the usual care group ( 1.9 vs 0.9 g/dL , P = 0.01 ) , and a shorter length of stay ( 7.0 vs 9.7 d , P = 0.026 ) . There was no difference in discharge Hb levels , morbidity , mortality , or quality of life . Conclusions : Administration of perioperative IV iron reduces the need for blood transfusion , and is associated with a shorter hospital stay , enhanced restoration of iron stores , and a higher mean Hb concentration 4 weeks after surgery OBJECTIVE There have been three r and omized , placebo-controlled , double-blind studies of intravenous iron in restless legs syndrome ( RLS ) , with differing outcomes . The one positive study used ferric carboxymaltose ( FCM ) at a total dose of 1000 mg . The purpose of this study was to replicate and extend the findings from the prior FCM study . METHODS Non-anemic , idiopathic RLS patients were enrolled in a r and omized , double-blinded , placebo-controlled study and received either 1000 mg FCM or placebo as a single infusion ( phase I ) . Subjects were off any RLS medications for at least two weeks prior to baseline assessment . The primary outcome variable was change from baseline at week 6 on the International Restless Legs Syndrome Severity ( IRLSS ) scale and a subject-completed , visual analog scale ( VAS ) of severity . Phase II of the study involved long-term ( 30 weeks ) follow-up after completion of the six-week efficacy phase . RESULTS At week 6 postinfusion , FCM compared to placebo recipients showed significantly greater change from baseline for both primary outcome measures ( IRLSS scale , -11.9 ± 8.04 vs -7.88 ± 5.89 , p = 0.03 ; VAS , -40.6 ± 22.7 vs -21.3 ± 20.0 , p = 0.001 ) . None of the secondary outcome variables showed a significant difference at week 6 . After six weeks of treatment , the FCM group had 19 ( 59.4 % ) responders , of which 12 had IRLSS scores < 10 ( " remitters " ) . Twelve ( 37.5 % ) of the 32 subjects treated with iron in phase I remained free of further RLS medications at 30 weeks . There were no serious adverse events observed in this study . CONCLUSION Two studies now support the value of FCM treatment both in the short term ( six weeks ) and long term ( 30 weeks ) for improving RLS symptoms This is the first study to investigate the efficacy of intravenous iron in treating fatigue in nonanemic patients with low serum ferritin concentration . In a r and omized , double-blinded , placebo-controlled study , 90 premenopausal women presenting with fatigue , serum ferritin ≤ 50 ng/mL , and hemoglobin ≥ 120 g/L were r and omized to receive either 800 mg of intravenous iron (III)-hydroxide sucrose or intravenous placebo . Fatigue and serum iron status were assessed at baseline and after 6 and 12 weeks . Median fatigue at baseline was 4.5 ( on a 0 - 10 scale ) . Fatigue decreased during the initial 6 weeks by 1.1 in the iron group compared with 0.7 in the placebo group ( P = .07 ) . Efficacy of iron was bound to depleted iron stores : In patients with baseline serum ferritin ≤ 15 ng/mL  , fatigue decreased by 1.8 in the iron group compared with 0.4 in the placebo group ( P = .005 ) , and 82 % of iron-treated compared with 47 % of placebo-treated patients reported improved fatigue ( P = .03 ) . Drug-associated adverse events were observed in 21 % of iron-treated patients and in 7 % of placebo-treated patients ( P = .05 ) ; none of these events was serious . Intravenous administration of  iron improved fatigue in iron-deficient , nonanemic women with a good safety and tolerability profile . The efficacy of intravenous iron was bound to a serum ferritin concentration ≤ 15 ng/mL. This study was registered at the International St and ard R and omized Controlled Trial Number Register ( www.is rct n.org ) as IS RCT N78430425 Background Unexplained fatigue is often left untreated or treated with antidepressants . This r and omized , 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 . Methods 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 Switzerl and , blinded to the study drug and r and omized ( computer-generated r and omization 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 ) . Results 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 . Conclusion 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 can not 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 . Trial Registration Clinical Trials.gov Background : Secondary thrombocytosis is a common clinical feature . In patients with cancer , it is a risk factor for venous thromboembolic events . In inflammatory bowel disease ( IBD ) , thrombocytosis is so far considered a marker of active disease and may contribute to the increased thromboembolic risk in this population . Observed effects of iron therapy on normalization of platelet counts led us to hypothesize that iron itself may regulate megakaryopoiesis . Here , we want to test the effect of iron replacement on platelet count and activity in IBD-associated thrombocytosis . Methods : We performed a r and omized , single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose ( FCM ) in patients with IBD with secondary thrombocytosis ( platelets > 450 G/L ) . Changes in platelet counts , hemoglobin , iron parameters , disease activity , megakaryopoietic growth factors , erythropoietin , and platelet activity were assessed . Patients received placebo or up to 1500 mg iron as FCM . Endpoints were evaluated at week 6 . Results : A total of 26 patients were included in the study , 15 patients were available for the per protocol analysis . A drop in platelets > 25 % ( primary endpoint ) was observed in 4 of 8 ( 50 % , iron group ) and 1 of 7 patients ( 14 % , placebo group , P = 0.143 ) . Mean platelet counts dropped on FCM but not on placebo ( 536 G/L to 411 G/L versus 580 G/L to 559 G/L ; P = 0.002 ) . Disease activity and megakaryopoietic growth factors remained unchanged and hemoglobin and iron parameters increased on FCM . The normalization of platelet counts was associated with a decrease in platelet aggregation and P-selectin expression . Conclusion : FCM lowers platelet counts and platelet activation in patients with IBD-associated secondary thrombocytosis CONTEXT Hypoxia is a major cause of pulmonary hypertension in respiratory disease and at high altitude . Recent work has established that the effect of hypoxia on pulmonary arterial pressure may depend on iron status , possibly acting through the transcription factor hypoxia-inducible factor , but the pathophysiological and clinical importance of this interaction is unknown . OBJECTIVE To determine whether increasing or decreasing iron availability modifies altitude-induced hypoxic pulmonary hypertension . DESIGN , SETTING , AND PARTICIPANTS Two r and omized , double-blind , placebo-controlled protocol s conducted in October-November 2008 . In the first protocol , 22 healthy sea-level resident men ( aged 19 - 60 years ) were studied over 1 week of hypoxia at Cerro de Pasco , Peru ( altitude 4340 m ) . In the second protocol , 11 high-altitude resident men ( aged 30 - 59 years ) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco , Peru . INTERVENTION In the first protocol , participants received intravenous infusions of Fe(III)-hydroxide sucrose ( 200 mg ) or placebo on the third day of hypoxia . In the second protocol , patients underwent staged isovolemic venesection of 2 L of blood . Two weeks later , patients received intravenous infusions of Fe(III)-hydroxide sucrose ( 400 mg ) or placebo , which were subsequently crossed over . MAIN OUTCOME MEASURE Effect of varying iron availability on pulmonary artery systolic pressure ( PASP ) assessed by Doppler echocardiography . RESULTS In the sea-level resident protocol , approximately 40 % of the pulmonary hypertensive response to hypoxia was reversed by infusion of iron , which reduced PASP by 6 mm Hg ( 95 % confidence interval [ CI ] , 4 - 8 mm Hg ) , from 37 mm Hg ( 95 % CI , 34 - 40 mm Hg ) to 31 mm Hg ( 95 % CI , 29 - 33 mm Hg ; P = .01 ) . In the chronic mountain sickness protocol , progressive iron deficiency induced by venesection was associated with an approximately 25 % increase in PASP of 9 mm Hg ( 95 % CI , 4 - 14 mm Hg ) , from 37 mm Hg ( 95 % CI , 30 - 44 mm Hg ) to 46 mm Hg ( 95 % CI , 40 - 52 mm Hg ; P = .003 ) . During the subsequent crossover period , no acute effect of iron replacement on PASP was detected . CONCLUSION Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00952302 Abstract Objective . Iron isomaltoside 1000 ( Monofer ® ) is a high-dose intravenous ( IV ) iron , which in a recent 8 weeks trial in inflammatory bowel disease ( IBD ) subjects with iron deficiency anemia ( IDA ) demonstrated good tolerability and efficacy . The present trial is an extension to this trial , which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin ( Hb ) ≥12.0 g/dl . Material and methods . This was a prospect i ve , open-label , 12 months trial of European IBD subjects willing to participate after completing the lead-in trial . Subjects were allowed re-dosing with 500–2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm . Outcome measures included Hb , safety parameters and need for additional iron dosing . Results . A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g ( mean cumulative dose 2.2 g ) . The mean ( SD ) Hb was 12.3 ( 1.5 ) g/dl at baseline , 12.8 ( 1.6 ) g/dl at 3 months , 12.8 ( 1.6 ) g/dl at 6 months , 12.9 ( 1.4 ) g/dl at 9 months and 12.9 ( 1.6 ) g/dl at 12 months . Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months . Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects , who recovered without sequelae . Conclusion . Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues . Trial registration : Clinical Trial.gov identifier : NCT01410435 Background Restless legs syndrome ( RLS ) is a common disorder in hemodialysis ( HD ) patients that causes sleep disturbances and diminished quality of life . Because iron deficiency has been implicated in the pathogenesis of RLS , we sought to investigate the effects of intravenous ( IV ) iron sucrose on symptoms of RLS in HD patients . Material / Methods The study was a r and omized , placebo-controlled study of 1000 mg iron sucrose versus normal saline as placebo . Patients were evaluated at baseline and 2 weeks after the last injection . The severity of RLS was assessed using the International RLS Study Group rating scale ( IRLS ) . Blood sample s were taken to measure iron parameters reflecting the iron status , including serum ferritin ( SF ) concentration , percentage transferrin saturation ( TSAT% ) and hemoglobin ( Hb ) , and other biochemical parameters as safety assessment s , including creatinine ( Cr ) , urea , intact parathyroid hormone ( iPTH ) , and the index of urea clearance ( Kt/V ) . Adverse events were monitored in all subjects during the period of infusion . Results After 2 weeks , IRLS scores decreased more in the IV-iron group ( −7.38±2.03 ) than in the placebo group ( −0.81±2.61 ) ( P=0.000 ) . Serum ferritin , TSAT , and hemoglobin increased more in the IV-iron group ( 227.63±77.64 μg/L ; 26.06±7.77 % ; 13.98±3.62g/L , respectively ) than in the placebo group ( SF , p=0.000 ; TSAT , p=0.000 ; Hb , p=0.000 , respectively ) . There were no significant differences between IV-iron and placebo groups in Cr , urea , iPTH , and Kt/V. No adverse effects were observed in the study . Conclusions IV iron sucrose is a safe and effective treatment for reducing RLS symptoms in HD patients over the short-term Background : It is intriguing and imperative that the comparison of the iron preparations in hemodialysis ( HD ) patients . This study aim ed to observe the short-term efficacy of parenteral iron sucrose and ferric chloride in HD patients . Material s and Methods : This was a consecutive 10-week single-blind study in Taiwan . An intravenous iron supplement of 100 mg/week was administered as an infusion in 100 ml of normal saline , until a total dose of 1000 mg was achieved . The primary outcome was evaluated by the changes in serum hematocrit ( Hct ) levels . The changes in serum Hct and iron indices were evaluated every 2 weeks for 10 weeks . The results were collected from 21 April to 4 July 2013 . Results : A total of 56 HD patients completed the study . Subjects were r and omized into an iron sucrose group ( 26 patients ) and a ferric chloride group ( 30 patients ) . Between the two treatment groups , there were no statistically significant differences in the change in serum Hct , ferritin , iron , or total iron binding capacity ( P > 0.05 ) . In the iron sucrose group , the increase in Hct levels was statistically significant at weeks 4 , 8 , and 10 . In the ferric chloride group , the increase in Hct levels was statistically significant at week 8 . No obvious major side effects were observed in both groups . Conclusion : In the study subjects , parenteral iron sucrose was as effective and safe as ferric chloride for treating anemia in HD patients Aims Patients with chronic heart failure ( CHF ) show impaired health-related quality of life ( HRQoL ) , an important target for therapeutic intervention . Impaired iron homeostasis may be one mechanism underlying the poor physical condition of CHF patients . This detailed sub analysis of the previously published FAIR-HF study evaluated baseline HRQoL in iron-deficient patients with CHF and the effect of intravenous ferric carboxymaltose ( FCM ) on HRQoL. Methods and results FAIR-HF r and omized 459 patients with reduced left ventricular ejection fraction and iron deficiency , with or without anaemia , to FCM or placebo ( 2:1 ) . Health-related quality of life was assessed at baseline and after 4 , 12 , and 24 weeks of therapy using the generic EQ-5D question naire and disease-specific Kansas City Cardiomyopathy Question naire ( KCCQ ) . Baseline mean Visual Analogue Scale ( VAS ) score was 54.3 ± 16.4 and KCCQ overall summary score was 52.4 ± 18.8 . Ferric carboxymaltose significantly improved VAS and KCCQ ( mean differences from baseline in KCCQ overall , clinical and total symptom scores , P < 0.001 vs. placebo ) at all time points . At Week 24 , significant improvement vs. placebo was observed in four of the five EQ-5D dimensions : mobility ( P= 0.004 ) , self-care ( P < 0.001 ) , pain/discomfort ( P= 0.006 ) , anxiety/depression ( P= 0.012 ) , and usual activity  ( P= 0.035 ) . Ferric carboxymaltose improved all KCCQ domain mean scores from Week 4 onward ( P≤ 0.05 ) , except for self-efficacy and social limitation . Effects were present in both anaemic and non-anaemic patients . Conclusions HRQoL is impaired in iron-deficient patients with CHF .  Intravenous FCM significantly improved HRQoL after 4 weeks , and throughout the remaining study period . The positive effects of FCM were independent of anaemia status Background and Objectives This trial explores whether intravenous iron isomaltoside 1000 ( Monofer ® ) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery . Study Design and Methods The trial is a prospect i ve , double-blind , comparative , placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery . The patients were r and omized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo . Results Mean preoperative haemoglobin in the active treatment group was 14·3 g/dl vs. 14·0 g/dl in the placebo group . At discharge 5 days after surgery , haemoglobin levels were reduced to 10·7 and 10·5 g/dl , respectively . One month after surgery , haemoglobin concentration had increased to an average of 12·6 g/dl vs. 11·8 g/dl ( p = 0·012 ) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group ( 38·5 % vs. 8·0 % ; p = 0·019 ) . There were no differences in side-effects between the groups . Conclusion A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery , with a short-term safety profile similar to placebo . Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed BACKGROUND Diagnosis of iron deficiency in hemodialysis patients is limited by the inaccuracy of commonly used tests . Reticulocyte hemoglobin content ( CHr ) is a test that has shown promise for improved diagnosis in preliminary studies . The purpose of this study was to compare iron management guided by serum ferritin and transferrin saturation to management guided by CHr . METHODS A total of 157 hemodialysis patients from three centers were r and omized to iron management  based on ( group 1 ) serum ferritin and transferrin saturation , or ( group 2 ) CHr . Patients were followed for six months . Treatment with intravenous iron dextran , 100 mg for 10 consecutive treatments was initiated if ( group 1 ) serum ferritin < 100 ng/mL or transferrin saturation < 20 % , or ( group 2 ) CHr < 29 pg . RESULTS There was no significant difference between groups in the final mean hematocrit or epoetin dose . The mean weekly dose of iron dextran was 47.7 + /- 35.5 mg in group 1 compared to 22.9 + /- 20.5 mg in group 2 ( P = 0.02 ) . The final mean serum ferritin was 399.5 + /- 247.6 ng/mL in group 1 compared to 304.7 + /- 290.6 ng/mL in group 2 ( P < 0.05 ) . There was no significant difference in final TSAT or CHr . Coefficient of variation was significantly lower for CHr than serum ferritin and transferrin saturation ( 3.4 % vs. 43.6 % and 39.5 % , respectively ) . CONCLUSIONS CHr is a markedly more stable analyte than serum ferritin or transferrin saturation , and iron management based on CHr results in similar hematocrit and epoetin dosing while significantly reducing IV iron exposure Background Intravenous iron therapy is a treatment option for iron deficient patients who are intolerant to oral iron or where oral iron is ineffective , but with possible adverse effects . Currently , prospect i ve studies comparing different intravenous iron formulations are needed to determine safety and efficacy of these agents . Methods We conducted a prospect i ve , double-blind , r and omized controlled trial ( RCT ) to assess the feasibility of a trial comparing the safety of high molecular weight intravenous iron dextran , Infufer ® , with intravenous iron sucrose , Venofer ® , in non-hemodialysis adult out patients . Primary outcome was the occurrence of immediate severe drug reactions . Results We enrolled 143 patients in a one-year period . Overall , 45/143 ( 31.5 % ) patients ( 20 iron dextran , 25 iron sucrose ) developed 48 infusion reactions ( 14 immediate , 28 delayed , and 3 both ) . The risk of an immediate reaction was similar in both groups , 9/73 ( 12.3 % ) iron dextran versus 8/70 ( 11.4 % ) iron sucrose , RR = 0.93 ( 95 % CI ; 0.38 to 2.27 ) . The risk of a delayed reaction was significantly higher in the iron sucrose group 22/70 ( 31.4 % ) versus the iron dextran group 9/73 ( 12.3 % ) , RR = 2.55 ( 95 % CI ; 1.26 to 5.15 ; p = 0.0078 ) . Conclusion In this limited feasibility study , no major differences in immediate reactions were seen , but a significantly higher number of delayed reactions were seen in the iron sucrose group . Further , under our assumptions and design a full RCT to evaluate the safety of different intravenous iron preparations is not feasible . Future studies should consider modifying the clinical outcomes , utilize multiple centers , and consider other emerging parenteral iron formulations . ( Clinical Trials.gov NCT005936197 January 3 , 2008 ) OBJECTIVE Intravenous ( IV ) iron has been used as a treatment to reduce Restless Legs Syndrome ( RLS ) symptoms , but two double-blinded trials of a frequently prescribed IV iron formulation , iron sucrose , failed to show lasting efficacy . This study evaluates efficacy and safety of a new IV iron formulation ( ferric carboxymaltose , FCM ) with molecular properties that may make iron more available for uptake to the brain than iron sucrose does . METHODS In this 28-day , multi-centre , r and omised , placebo-controlled trial 46 RLS patients were discontinued from all RLS treatment . Twenty-four received 500 mg FCM in two doses 5 days apart and 22 received a matching placebo . At day 28 , those on placebo were given a single 1000 mg IV FCM and those not responding to initial treatment were given a third dose of 500 mg FCM . Patients were followed up for 24 weeks or until needing added RLS treatment . RESULTS FCM significantly improved primary and secondary outcomes compared to placebo :  International Restless Legs Syndrome study group severity scale ( IRLS ) average ( SD ) decrease of 8.9 ( 8.52 ) versus 4.0 ( 6.11 ) , p=0.040 ; Clinical Global Inventory of Change ( CGI-1 ) very much or much improved 48.3 % versus 14.3 % , p=0.004 . Quality of life was also significantly improved . Of the 24 with initial iron treatment 45 % responded and 29 % remitted ( IRLS ≤ 10 ) at day 28 , and 25 % continued free of other RLS medications at 24 weeks after treatment . The single 1000 mg dose on day 28 produced the same degree of treatment response as the divided dose , but the added 500 mg dose for those not responding to the initial treatment showed little benefit . There were no significant adverse events . CONCLUSIONS IV FCM  provided a safe and effective treatment for RLS that lasted for at least 24 weeks for some patients . Larger studies are needed to confirm these results BACKGROUND Anemia in heart failure patients and has been associated with increased morbi-mortality . Previous studies have treated anemia in heart failure patients with either erythropoietin alone or combination of erythropoietin and intravenous ( i.v . ) iron . However , the effect of i.v . or oral ( p.o . ) iron supplementation alone in heart failure patients with anemia was virtually unknown . AIM To compare , in a double-blind design , the effects of i.v . iron versus p.o . iron in anemic heart failure patients . METHODS IRON-HF study was a multicenter , investigator initiated , r and omized , double-blind , placebo controlled trial that enrolled anemic heart failure patients with preserved renal function , low transferrin saturation ( TSat ) and low-to-moderately elevated ferritin levels . Interventions were Iron Sucrose i.v . 200 mg , once a week , for 5 weeks , ferrous sulfate 200 mg p.o . TID , for 8 weeks , or placebo . Primary endpoint was variation of peak oxygen consumption ( peak VO2 ) assessed by ergospirometry over 3 month follow-up . RESULTS Eighteen patients had full follow-up data . There was an increment of 3.5 ml/kg/min in peak VO2 in the i.v . iron group . There was no increment in peak VO2 in the p.o . iron group . Patients ' ferritin and TSat increased significantly in both treated groups . Hemoglobin increased similarly in all groups . CONCLUSION I.v . iron seems to be superior in improving functional capacity  of heart failure patients . However , correction of anemia seems to be at least similar between p.o . iron and i.v . iron supplementation Iron deficiency may exacerbate symptoms in the Restless Legs Syndrome ( RLS ) . We investigated the effect of intravenous iron sucrose or placebo on symptoms in patients with RLS and mild to moderate iron deficit . Sixty patients with primary RLS ( seven males , age 46 ( 9 ) years , S-ferritin < or = 45 microg/L ) recruited from a cohort of 231 patients were r and omly assigned in a 12-months double-blind , multi-centre study of iron sucrose 1000 mg ( n = 29 ) or saline ( n = 31 ) . The primary efficacy variable was the RLS severity scale ( IRLS ) score at week 11 . Median IRLS score decreased from 24 to 7 ( week 11 ) after iron sucrose and from 26 to 17 after placebo ( P = 0.123 , N.S. for between treatment comparison ) . The corresponding scores at week 7 were 12 and 20 in the two groups ( P = 0.017 ) . Drop out rate because of lack of efficacy at 12 months was 19/31 after placebo and 5/29 patients after iron sucrose ( Kaplan-Meier estimate , log rank test P = 0.0006 ) suggesting an iron induced superior long term RLS symptom control . Iron sucrose was well tolerated . This study showed a lack of superiority of iron sucrose at 11 weeks but found evidence that iron sucrose reduced RLS symptoms both in the acute phase ( 7 weeks ) and during long-term follow up in patients with variable degree of iron deficiency . Further studies on target patient groups , dosing and dosing intervals are warranted before iron sucrose could be considered for treatment of iron deficient patients with RLS BACKGROUND AND OBJECTIVE Non-anaemic iron deficiency ( NAID ) might alter the oxygen pathway in health and disease . The current study aims at assessing the impact of NAID on aerobic capacity in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS A prospect i ve sample of 70 non-anaemic COPD patients c and i date to participate in an 8-week pulmonary rehabilitation ( PR ) programme  was studied . Incremental cycling exercise to peak oxygen uptake ( V'O2peak ) and constant work-rate exercise at 80 % V'O2peak to exhaustion were assessed pre- and post-PR . Training-induced increase of endurance time ( ET ) ≥33 % , which represented the minimal clinical ly important difference , classified patients as responders to exercise training . RESULTS The prevalence of NAID was 48 % ( n = 34 ) showing no relationship with the Global Initiative for Chronic Obstructive Lung Disease stages ( P = 0.209 ) . Patients with NAID showed lower pre-training ET ( P = 0.033 ) and V'O2peak ( P = 0.007 ) than normal iron status ( NIS ) patients after adjustment for potential covariates . Significant training-induced physiological changes were seen in the NIS group ( ΔV'O2peak 68(132 ) mL/min ; P = 0.009 ) , but not in the NAID group ( ΔV'O2peak 26 ( 126 ) mL/min ; P = 0.269 ) . The NAID group showed lower percentage of responders to training ( 56 % ) than the NIS group ( 78 % ) ( P = 0.041 ) . CONCLUSIONS COPD patients with NAID showed lower pre-training aerobic capacity and reduced training-induced response than NIS patients after adjusting for potential confounding variables Abstract Objective : Parenteral sodium ferric gluconate in complex ( Ferrlecit [ br and ed SFG ] ) is used to treat patients with iron deficiency anemia undergoing chronic hemodialysis and receiving supplemental epoetin . This comparative pharmacokinetic study ( GeneraMedix , Inc. , Study 17909 ) evaluates whether the recently approved generic product Nulecit ( generic SFG ) and the br and ed product Ferrlecit ( br and ed SFG ) are bioequivalent . Methods : In this open-label study , 240 healthy volunteers in a fasting state were assigned r and omly to a single 10-min intravenous ( IV ) infusion of 125 mg of generic or br and ed SFG .  Total and transferrin-bound iron concentrations were determined for the 36-h period after infusion and corrected for pretreatment levels . Maximum concentration ( Cmax ) and area under the concentration – time curve of 0 to 36 h ( AUC[0–36 ] ) were compared between the two products . Demonstration of bioequivalence required that the 90 % confidence intervals of each parameter evaluated for generic SFG were within 80 % to 125 % of the corresponding values for br and ed SFG . Results : Uncorrected and baseline-corrected mean serum concentrations of total serum iron during the 36-h assessment period were similar for generic and br and ed SFG . For total serum iron , the geometric mean ratios of corrected Cmax and AUC[0–36 ] were 100 % . For transferrin-bound iron , the geometric mean ratios were 87 % for corrected Cmax and 92 % for corrected AUC[0–36 ] . All associated 90 % confidence intervals were within the range of 80 % to 125 % . Conclusions : A new generic SFG in complex for IV infusion is bioequivalent to the br and ed SFG in complex for IV infusion . The generic SFG is AB rated by the FDA and considered therapeutically equivalent to the br and ed product Purpose Both anaemia and allogenic red blood cell transfusion are common and potentially harmful in patients admitted to the intensive care unit . Whilst intravenous iron may decrease anaemia and RBC transfusion requirement , the safety and efficacy of administering iron intravenously to critically ill patients is uncertain . Methods The multicentre , r and omized , placebo-controlled , blinded Intravenous Iron or Placebo for Anaemia in Intensive Care ( IRONMAN ) study was design ed to test the hypothesis that , in anaemic critically ill patients admitted to the intensive care unit , early administration of intravenous iron , compared with placebo , reduces allogeneic red blood cell transfusion during hospital stay and increases the haemoglobin level at the time of hospital discharge . Results Of 140 patients enrolled , 70 were assigned to intravenous iron and 70 to placebo . The iron group received 97 red blood cell units versus 136 red blood cell units in the placebo group , yielding an incidence rate ratio of 0.71 [ 95 % confidence interval ( 0.43–1.18 ) , P = 0.19 ] . Overall , median haemoglobin at hospital discharge was significantly higher in the intravenous iron group than in the placebo group [ 107 ( interquartile ratio IQR 97–115 ) vs. 100 g/L ( IQR 89–111 ) , P = 0.02 ] . There was no significant difference between the groups in any safety outcome . Conclusions In patients admitted to the intensive care unit who were anaemic , intravenous iron , compared with placebo , did not result in a significant lowering of red blood cell transfusion requirement during hospital stay . Patients who received intravenous iron had a significantly higher haemoglobin concentration at hospital discharge . The trial was registered at http://www.anzctr.org.au as # ACTRN12612001249842 This investigation examined the effect of intramuscular iron injections on aerobic-exercise performance in iron-deficient women . Sixteen athletes performed a 10-min steady-state submaximal economy test , a VO2max test , and a timed test to exhaustion at VO2max workload . Subjects were r and omly assigned to an iron-supplemented group ( IG ) receiving intramuscular iron injections or to a placebo group ( PG ) . Twenty days after the first injection , exercise and blood testing were repeated . A final blood test occurred on Day 28 . Post supplementation , no differences were found between the groups ' submaximal or maximal VO2 , heart rate , or blood lactate ( P > 0.05 ) . Time to exhaustion was increased in the IG ( P < 0.05 ) but was not greater than that of the PG ( P > 0.05 ) . The IG 's serum ferritin ( SF ) was significantly increased on Days 20 and 28 ( mean + /- st and ard error : 19 + /- 3 to 65 + /- 11 to 57 + /- 12 microg/L ; P < 0.01 ) , with a percentage change from baseline significantly greater than in the PG ( P < 0.01 ) . It was concluded that intramuscular iron injections can effectively increase SF without enhancing submaximal or maximal aerobic-exercise performance in iron-depleted female athletes BACKGROUND Restless legs syndrome ( RLS ) is a common disorder in patients with end-stage renal disease ( ESRD ) that causes motor agitation and insomnia . Because RLS has been associated with iron deficiency , we sought to investigate the effects of intravenous ( IV ) iron dextran on symptoms of RLS in a double-blind placebo-controlled trial . METHODS Patients determined to have RLS by International RLS Study Group criteria were administered either iron dextran , 1,000 mg , or normal saline IV in a blinded fashion . Patient demographic data were collected , and blood chemistry tests , liver function studies , serum iron levels , ferritin levels , and total iron-binding capacity were obtained at baseline and 1 , 2 , and 4 weeks postinfusion . Side effects or adverse events to interventions were monitored , and RLS symptoms were assessed by a rating scale at the same intervals . RESULTS Eleven patients were r and omly assigned to the administration of iron dextran , and 14 patients to the administration of saline .  RLS severity scores were slightly higher in the placebo group at baseline , but hemoglobin levels , iron stores , and other biochemical parameters did not differ . Although no change in symptoms were seen in the placebo-treated group , significant improvement in RLS symptom scores in response to iron dextran was seen 1 week after infusion ( -2 ; interquartile range [ IQR ] , -6 to -1 ; P = 0.03 , Wilcoxon 's rank sums ) , but was greatest at 2 weeks ( -3 ; IQR , -5 to -2 compared with -1 to 0 ; P = 0.01 ) . Salutary effects of iron persisted at 4 weeks , but were no longer statistically significant . The significant increase in serum ferritin levels and iron saturation observed in the iron dextran-treated group was not seen in the placebo-treated group . No differences in adverse events were noted between groups . CONCLUSION High-dose iron dextran infusion is associated with a significant , but transient , reduction in symptoms of RLS in patients with ESRD Abstract Background : Compromised iron status is important in restless legs syndrome pathophysiology . We compared the efficacy and tolerability of ferric carboxymaltose ( single intravenous dose ) versus placebo for restless legs syndrome treatment in iron‐deficient nonanemic patients . Methods : Patients with moderate to severe restless legs syndrome and serum ferritin < 75 μg/L ( or serum ferritin 75‐300 μg/L and transferrin saturation < 20 % ) were r and omized to ferric carboxymaltose ( 1000 mg iron ) or placebo . Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point ; week 12 was a secondary end point . Results : Ferric carboxymaltose treatment ( n = 59 ) led to nonsignificant improvement over placebo ( n = 51 ) in International Restless Legs Syndrome Severity Scale score at week 4 ( difference [ 95 % confidence interval ] , ‐2.5 [ ‐5.93 to 1.02 ] , P = 0.163 ) , reaching significance by week 12 ( ‐4.66 [ ‐8.59 to ‐0.73 ] , P = 0.021 ) . Conclusions : In patients who responded to treatment , ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed . © 2017 The Authors . Movement Disorders published by Wiley Periodicals , Inc. on behalf of International Parkinson and Movement Disorder Society BACKGROUND Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption . However , daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses . Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing . METHODS We did two prospect i ve , open-label , r and omised controlled trials assessing iron absorption using (54Fe)-labelled , (57Fe)-labelled , or (58Fe)-labelled ferrous sulfate in iron-depleted ( serum ferritin ≤25 μg/L ) women aged 18 - 40 years recruited from ETH Zurich and the University of Zurich , Switzerl and . In study 1 , women were r and omly assigned ( 1:1 ) to two groups . One group was given 60 mg iron at 0800 h ( ±1 h ) on consecutive days for 14 days , and the other group was given the same doses on alternate days for 28 days . In study 2 , women were assigned to two groups , stratified by serum ferritin so that two groups with similar iron statuses could be formed . One group was given 120 mg iron at 0800 h ( ±1 h ) and the other was given the dose split into two divided doses of 60 mg at 0800 h ( ±1 h ) and 1700 h ( ±1 h ) for three consecutive days . 14 days after the final dose , the groups were each crossed over to the other regimen . Within-individual comparisons were done . The co- primary outcomes in both studies were iron bioavailability ( total and fractional iron absorption ) , assessed by measuring the isotopic label abundance in erythrocytes 14 days after administration , and serum hepcidin . Group allocations in both studies were not masked and primary and safety analyses were done on an intention-to-treat basis . The studies were registered at Clinical Trials.gov , numbers NCT02175888 ( study 1 ) and NCT02177851 ( study 2 ) and are complete . FINDINGS For study 1 , 40 women were enrolled on Oct 15 - 29 , 2015 . 21 women were assigned to the consecutive-day group and 19 to the alternate-day group . At the end of treatment ( 14 days for the consecutive-day group and 28 days for the alternate-day group ) , geometric mean ( -SD , + SD ) cumulative fractional iron absorptions were 16·3 % ( 9·3 , 28·8 ) in the consecutive-day group versus 21·8 % ( 13·7 , 34·6 ) in the alternate-day group ( p=0·0013 ) , and cumulative total iron absorption was 131·0 mg ( 71·4 , 240·5 ) versus 175·3 mg ( 110·3 , 278·5 ; p=0·0010 ) . During the first 14 days of supplementation in both groups , serum hepcidin was higher in the consecutive-day group than the alternate-day group ( p=0·0031 ) . In study 2 , 20 women were enrolled between Aug 13 and 18 , 2015 . Ten women were assigned to receive once-daily dosing and ten were assigned to receive twice-daily divided dosing . No significant differences were seen in fractional ( day 1 - 3 geometric mean : 11·8 % [ 7·1 , 19·4 ] once daily vs 13·1 % [ 8·2 , 20·7 ] twice daily ; p=0·33 ) or total iron absorption ( day 1 - 3 : 44·3 mg [ 29·4 , 66·7 ] once daily vs 49·4 [ 35·2 , 69·4 ] twice daily ; p=0·33 ) between the two dosing regimens . Twice-daily divided doses result ed in a higher serum hepcidin concentration than once-daily dosing ( p=0·013 ) . No grade 3 or 4 adverse events were reported in either study . INTERPRETATION In iron-depleted women , providing iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption . Providing iron supplements on alternate days and in single doses optimises iron absorption and might be a preferable dosing regimen . These findings should be confirmed in iron-deficient anaemic patients . FUNDING Swiss National Science Foundation , Bern , Switzerl and Introduction This study sought to compare efficacy and safety of ferric carboxymaltose vs. placebo in iron-deficient patients with fibromyalgia . Methods This blinded , placebo-controlled , phase 2 study r and omized adults with fibromyalgia and Revised Fibromyalgia Impact Question naire ( FIQR ) scores ≥ 60 , ferritin levels < 0.05 µg/ml , and transferrin saturation < 20 % ( 1:1 ) to receive ferric carboxymaltose [ 15 mg/kg ( up to 750 mg ) ] , or placebo ( 15 cc  normal saline ) intravenously on study days 0 and 5 . Patients visited the clinic on days 14 , 28 , and 42 for efficacy and safety assessment s. The primary efficacy endpoint was proportion of patients with a ≥ 13-point improvement from baseline to day 42 in FIQR scale score . Secondary endpoints included changes from baseline in FIQR scale , Brief Pain Inventory ( BPI ) total score , Medical Outcomes Study ( MOS ) Sleep scale , Fatigue Visual Numeric Scale ( VNS ) , iron indices ( transferrin saturation and ferritin ) , and safety . Results The efficacy analysis group comprised 80 patients , and the safety analysis group comprised 81 .  More ferric carboxymaltose patients ( 77 % ) vs. placebo patients ( 67 % ) achieved the primary endpoint , but the difference was not significant . Greater improvements from baseline to day 42 were observed for ferric carboxymaltose vs. placebo in FIQR total score , BPI total score , Fatigue VNS score , and iron indices . Mean changes in MOS Sleep scale scores were similar between groups . Ferric carboxymaltose was safe and well tolerated . Conclusions Compared with placebo , ferric carboxymaltose improved measures of fibromyalgia severity and was well tolerated . The current results suggest that ferric carboxymaltose shows benefit in iron-deficient patients with concurrent fibromyalgia . Funding Luitpold Pharmaceuticals , Inc . Trial Registration Clinical Trials.gov identifier , NCT02409459 Intravenous ( iv ) iron administration is typically indicated in individuals who have iron deficiency refractory to oral iron . However , in certain chronic disease states , it may be beneficial to administer iv iron to individuals who are not strictly iron deficient . The purpose of this study was to define a dose-response relationship between clinical indices of iron status and modest loading with iv iron in healthy , iron-replete participants . This was a double-blind , controlled study involving 18 male participants . Participants were block r and omised 2:1 to the iron and saline ( control ) groups . Participants in the iron group received 250 mg of iv iron , once a month for six months , provided that their ferritin remained < 300 µg/L and their transferrin saturation remained < 45 % . Otherwise they received a saline infusion , as did the control participants . Iron indices were measured monthly during the study . The pulmonary vascular response to sustained hypoxia and total hemoglobin mass were measured before , at three months ( hemoglobin mass only ) and at six months , as variables that may be affected by iron loading . Serum ferritin was robustly elevated by iv iron by 0.21 µg/L/mg of iron delivered ( 95 % CI : 0.15 - 0.26 µg/L/mg ) , but the effects on all other iron indices did not reach statistical significance . The pulmonary vascular response to sustained hypoxia was significantly suppressed by iron loading at six months , but the hemoglobin mass was unaffected . We conclude that the robust effect on ferritin provides a quantitative measure for the degree of iron loading in iron-replete individuals BACKGROUND Iron repletion augments exercise capacity in chronic heart failure ( HF ) , but there is a lack of mechanistic data explaining how iron could augment exercise performance despite minimal changes in hemoglobin ( Hb ) . Besides Hb , iron is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine ( PCr ) . Dynamic phosphorus magnetic resonance spectroscopy is a noninvasive tool that quantifies in vivo muscle energetics by measuring the kinetics of PCr recovery after exertion . We tested the hypothesis that intravenous iron repletion in chronic HF enhances skeletal muscle energetics as reflected by shorter PCr recovery half-times ( PCr t1/2 ) on phosphorus magnetic resonance spectroscopy . METHODS We enrolled 40 patients ( 50 % anemic ) with chronic HF , New York Heart Association class ≥II , left ventricular ejection fraction ≤45 % , and iron deficiency ( ferritin<100 μg/L or 100 - 300 μg/L with transferrin saturation < 20 % ) . Subjects underwent stratified ( anemic versus nonanemic ) r and omization ( 1:1 ) to a single , double-blinded , total dose infusion of iron isomaltoside or saline placebo with end points reassessed early at 2 weeks posttreatment to minimize confounding from exercise adaptation . The primary end point was PCr t1/2 at 2 weeks . Secondary end points included ADP recovery half-time ( ADP t1/2 ; energetic marker ) , iron status , symptoms , Hb , exercise capacity , and safety . RESULTS In the total population , treatment groups were similar at baseline . At 2 weeks , iron isomaltoside  improved PCr t1/2 ( adjusted difference , -6.8 s ; 95 % CI , 11.5 to -2.1 ; P=0.006 ) , ADP t1/2 ( -5.3 s ; 95 % CI , -9.7 to -0.9 ; P=0.02 ) , ferritin ( 304 ng/mL ; 95 % CI , 217 - 391 ; P<0.0001 ) , transferrin saturation ( 6.8 % ; 95 % CI , 2.7 - 10.8 ; P=0.002 ) , New York Heart Association class ( -0.23 ; 95 % CI , -0.46 to -0.01 ; P=0.04 ) , resting respiratory rate ( -0.7 breaths/min ; 95 % CI , -1.2 to -0.2 ; P=0.009 ) , and postexercise Borg dyspnea score ( -2.0 ; 95 % CI , -3.7 to -0.3 ; P=0.04 ) , but not Hb ( 2.4 g/L ; 95 % CI , -3.5 to 8.4 ; P=0.41 ) . Adverse events were similar between groups . In subgroup analyses , iron isomaltoside improved PCr t1/2 in anemic ( -8.4 s ; 95 % CI , -16.7 to -0.2 ; P=0.04 ) and nonanemic ( -5.2 s ; 95 % CI , -10.6 to 0.2 ; P=0.06 ) cohorts . CONCLUSIONS In patients with chronic HF and iron deficiency , a total repletion dose of iron isomaltoside given at a single sitting is well tolerated and associated with faster skeletal muscle PCr t1/2 at 2 weeks , implying better mitochondrial function . Augmented skeletal muscle energetics might therefore be an important mechanism via which iron repletion confers benefits in chronic HF despite minimal Hb changes . CLINICAL TRIAL REGISTRATION URL : https://www . clinical trialsregister.eu/ctr- search /trial/2012 - 005592 - 13/GB . Unique identifier : EudraCT 2012 - 005592 - 13 Iron deficiency is common in colorectal cancer . Despite perioperative guidelines advocating for the correction of non-anaemic iron deficiency prior to major surgery , the impact of this pathology on postoperative outcome is unclear . We conducted a single-centre , historical cohort study of 141 elective resections for colorectal cancer . We stratified non-anaemic patients into iron deficient and iron replete groups , and collected data on baseline characteristics , preoperative laboratory results , intraoperative events and postoperative outcomes . As this study was an exploratory work for future research , a P-value of 0.25 was considered relevant . Patients in the deficient group demonstrated lower baseline ferritin ( median ( interquartile range , IQR ) 76 ( 41–141 ) µg/L versus 207 ( 140–334 ) µg/L , P < 0.001 ) and transferrin saturation ( mean ( st and ard deviation , SD ) 18 % ( 8 % ) versus 32 % ( 12 % ) , P < 0.001 ) than those in the replete group , and lower starting haemoglobin ( mean ( SD ) 138 ( 10 ) g/L versus 144 ( 12 ) g/L , P = 0.01 ) . The deficient group had increased re-admission ( 25 % ( 24 % ) versus 4 % ( 11 % ) , P = 0.15 ) and all-cause infection ( 25 % ( 24 % ) versus 5 % ( 14 % ) , P = 0.24 ) . A decrease of two days in days alive and out of hospital at postoperative day 90 was seen in the deficient group on univariate analysis ( median ( IQR ) 81 ( 75–84 ) versus 83 ( 78–84 ) , P = 0.25 ) . This reduced to 1.24 days in multivariate adjusted quantile regression analysis ( P = 0.22 ) . Days alive and out of hospital at day 90 , postoperative re-admission and postoperative infection may be meaningful outcome measures for future prospect i ve observational work examining non-anaemic iron deficiency in patients undergoing major surgery for colorectal cancer BACKGROUND Iron deficiency is frequent in patients undergoing cardiac surgery . The relevance of iron deficiency , however , is ill defined . Therefore , our study aim ed to investigate the impact of iron deficiency ( ferritin < 100 μg L-1 ) with or without concomitant anaemia on clinical outcome after cardiac surgery . METHODS In this prospect i ve observational study , 730 patients undergoing elective cardiac surgery were assigned into four groups according to their iron status and anaemia . Mortality , serious adverse events ( SAEs ) , major cardiac and cerebrovascular events ( MACCEs ) , allogenic blood transfusion requirements , and length of hospital stay were assessed during a 90-day follow-up period . The effect of iron deficiency on these outcomes was first calculated in models adjusting for anaemia only , followed by two multivariate models adjusting for anaemia and either the EuroSCORE II or any possible confounders . RESULTS The presence of iron deficiency ( ferritin < 100 μg L-1 ) was associated with an increase in 90-day mortality from 2 % to 5 % in patients without anaemia , and from 4 % to 14 % in patients with anaemia . Logistic regression result ed in an odds ratio of 3.5 ( 95 % confidence interval : 1.5 - 8.4 ) ; P=0.004 . The effect persisted in both multivariate models . Moreover , iron deficiency was associated with an increased incidence of SAEs , MACCEs , transfusion , and prolonged hospital stay . CONCLUSIONS Preoperative iron deficiency ( ferritin < 100 μg L-1 ) was independently associated with increased mortality , more SAEs , and prolonged hospital stay after cardiac surgery . These findings underline the importance of preoperative iron deficiency screening in the context of a comprehensive patient blood management programme , and highlight its importance as a research topic in cardiac surgery . CLINICAL TRIAL REGISTRATION NCT02031289 OBJECTIVES We tested the hypothesis that intravenous iron improves exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure ( CHF ) and iron deficiency . BACKGROUND Anemia is common in heart failure . Iron metabolism is disturbed , and administration of iron might improve both symptoms and exercise tolerance . METHODS We r and omized 35 patients with CHF ( age 64 + /- 13 years , peak oxygen consumption [ pVO2 ] 14.0 + /- 2.7 ml/kg/min ) to 16 weeks of intravenous iron ( 200 mg weekly until ferritin > 500 ng/ml , 200 mg monthly thereafter ) or no treatment  in a 2:1 ratio . Ferritin was required to be < 100 ng/ml or ferritin 100 to 300 ng/ml with transferrin saturation < 20 % . Patients were stratified according to hemoglobin levels ( < 12.5 g/dl [ anemic group ] vs. 12.5 to 14.5 g/dl [ nonanemic group ] ) . The observer-blinded primary end point was the change in absolute pVO2 . RESULTS The difference ( 95 % confidence interval [ CI ] ) in the mean changes from baseline to end of study between the iron and control groups was 273 ( 151 to 396 ) ng/ml for ferritin ( p < 0.0001 ) , 0.1 ( -0.8 to 0.9 ) g/dl for hemoglobin ( p = 0.9 ) , 96 ( -12 to 205 ) ml/min for absolute pVO2 ( p = 0.08 ) , 2.2 ( 0.5 to 4.0 ) ml/kg/min for pVO2/kg ( p = 0.01 ) , 60 ( -6 to 126 ) s for treadmill exercise duration ( p = 0.08 ) , -0.6 ( -0.9 to -0.2 ) for New York Heart Association ( NYHA ) functional class ( p = 0.007 ) , and 1.7 ( 0.7 to 2.6 ) for patient global assessment ( p = 0.002 ) . In anemic patients ( n = 18 ) , the difference ( 95 % CI ) was 204 ( 31 to 378 ) ml/min for absolute pVO2 ( p = 0.02 ) , and 3.9 ( 1.1 to 6.8 ) ml/kg/min for pVO2/kg ( p = 0.01 ) . In nonanemic patients , NYHA functional class improved ( p = 0.06 ) . Adverse events were similar . CONCLUSIONS Intravenous iron loading improved exercise capacity and symptoms in patients with CHF and evidence of abnormal iron metabolism . Benefits were more evident in anemic patients . ( Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure ; http://www . clinical trials.gov/ct/show/NCT00125996 ; NCT00125996 ) Background : Iron deficiency is common in patients with heart failure ( HF ) and is associated with reduced exercise capacity and poor outcomes . Whether correction of iron deficiency with ( intravenous ) ferric carboxymaltose ( FCM ) affects peak oxygen consumption [ peak VO2 ] , an objective measure of exercise intolerance in HF , has not been examined . Methods : We studied patients with systolic HF ( left ventricular ejection fraction ⩽45 % ) and mild to moderate symptoms despite optimal HF medication . Patients were r and omized 1:1 to treatment with FCM for 24 weeks or st and ard of care  . The primary end point was the change in peak VO2 from baseline to 24 weeks . Secondary end points included the effect on hematinic and cardiac biomarkers , quality of life , and safety . For the primary analysis , patients who died had a value of 0 imputed for 24-week peak VO2 . Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data . Results : A total of 172 patients with HF were studied and received FCM ( n=86 ) or st and ard of care ( control group , n=86 ) . At baseline , the groups were well matched ; mean age was 64 years , 75 % were male , mean left ventricular ejection fraction was 32 % , and peak VO2 was 13.5 mL/min/kg  . FCM  significantly increased serum ferritin and transferrin saturation . At 24 weeks , peak VO2 had decreased in the control group ( least square means −1.19±0.389 mL/min/kg ) but was maintained on FCM ( −0.16±0.387 mL/min/kg ; P=0.020 between groups ) . In a sensitivity analysis , in which missing data were not imputed , peak VO2 at 24 weeks decreased by −0.63±0.375 mL/min/kg in the control group and by −0.16±0.373 mL/min/kg in the FCM group ; P=0.23 between groups ) . Patients ’ global assessment and functional class as assessed by the New York Heart Association improved on FCM versus st and ard of care . Conclusions : Treatment with intravenous FCM in patients with HF and iron deficiency  improves iron stores . Although a favorable effect on peak VO2 was observed on FCM , compared with st and ard of care in the primary analysis , this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died . Whether FCM is associated with an improved outcome in these high-risk patients needs further study . Clinical Trial Registration : URL : http://www . clinical trials.gov . Unique identifier : NCT01394562
target: Quality -of-life scores ( Piper Fatigue Scale MD 0.73 , 95 % CI 0.29 to 1.18 ; I2 = 0 % ; studies = 3 ) and peak oxygen consumption ( MD 2.77 mL/kg/min , 95 % CI -0.89 to 6.43 ; I2 = 36 % ; 2 studies , 32 participants ) were associated with very low- quality evidence , and we remain uncertain about the role of intravenous iron for these metrics .
  Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient population s , beyond stating that it may result in a small , clinical ly insignificant increase in haemoglobin concentration .
background: BACKGROUND Iron deficiency is one of the most common nutritional deficiencies , and has a number of physiological manifestations .
  Early , or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity .
  Oral iron preparations have a high incidence of intolerable side effects , and are ineffective in certain forms of iron deficiency .
  Consequently , intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency .
  The newer , more stable iron preparations in particular purport to have a lower incidence of side effects , and are now used across a range of different patient population s. OBJECTIVES To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency .