Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial)
British journal of anaesthesia. 2022
BACKGROUND Preoperative anaemia is a risk factor for adverse postoperative outcomes after cardiac surgery. Iron deficiency is a frequent cause of low preoperative haemoglobin. An effective treatment for preoperative anaemia associated with iron deficiency has not been determined. METHODS We conducted a single-centre, open-label, pragmatic randomised trial, enrolling 156 elective cardiac surgery patients who had low preoperative haemoglobin (100-130 g L(-1)) with iron deficiency (serum ferritin <100 μg L(-1) or transferrin saturation <30%) to compare intravenous ferric derisomaltose 1000 mg and darbepoetin 200 μg subcutaneously (intervention group) with oral ferrous sulphate 600 mg daily (control group). The primary outcome was transfusion of at least one unit of allogeneic red cells during surgery and within the following 5 days. Secondary outcomes included the change in haemoglobin concentration between randomisation and surgery, red cell transfusion volume, postoperative blood loss, pre-specified postoperative complications, length of hospital stay, and in-hospital death. RESULTS The odds of red cell transfusion were lower in the intervention group compared with the control group (adjusted odds ratio=0.33; 95% confidence interval [CI], 0.15-0.75; P=0.008). Of the secondary outcomes, the only significant difference was the increase in haemoglobin between randomisation and surgery, intervention vs control 9.5 g L(-1) (95% CI, 6.8-12.2; P<0.001). CONCLUSIONS In patients with a low preoperative haemoglobin and iron deficiency, preoperative treatment with a single dose of ferric derisomaltose and darbepoetin decreased the proportion of participants who received a perioperative blood transfusion as a consequence of a greater increase in haemoglobin compared with treatment with oral ferrous sulphate. CLINICAL TRIAL REGISTRATION ISRCTN Number: 41421863; EUDRACT number: 2011-003695-36.
Effects of Iron Sucrose and Erythropoietin on Transfusion Requirements in Patients with Preoperative Iron Deficiency Anemia Undergoing on-Pump Coronary Artery Bypass Graft
The journal of Tehran Heart Center. 2022;17(1):7-14
Background: Preoperative anemia is an independent risk factor for higher rates of blood transfusion in cardiac surgery. This study aimed to evaluate the effects of intravenous iron sucrose and erythropoietin on transfusion requirements in patients with preoperative iron deficiency anemia (IDA) undergoing on-pump coronary artery bypass graft (CABG) surgery. Methods: In this open-label, randomized clinical trial, patients with preoperative IDA who were candidates for on-pump CABG were randomized into intervention (iron plus erythropoietin) or control groups. Iron sucrose was administered as a 200 mg intravenous dose and erythropoietin as a 100 IU/kg bolus 1 to 2 days before surgery. The primary outcome was the amount of blood transfusion during the first 4 postoperative days. Results: The study population consisted of 114 patients. The mean age was 64.11±8.18 years in the intervention group and 63.35±8.70 years in the control group. Twenty-seven patients (47.4%) in the intervention group and 25 (43.9%) in the control group were males. The number of red blood cell units transfused per patient exhibited a significant fall in the intervention group compared with the control group (P˂0.001). The ferritin level showed a significant rise in the intervention group on postoperative day 7 (P=0.027). The length of stay in the intensive care unit and the hospital was significantly lower in the intervention arm (P=0.041 and P=0.006, respectively). No adverse events were reported in both groups. Conclusion: The use of erythropoietin and iron sucrose 1 to 2 days before surgery significantly decreased the need for blood transfusion in patients with IDA undergoing CABG without any significant adverse events.
Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for TAVI Results of the IIISAS randomised trial
European journal of heart failure. 2022
AIMS: The aim of this trial was to evaluate whether intravenous iron could provide benefit beyond transcatheter aortic valve implantation (TAVI) in iron deficient patients with severe aortic stenosis. METHODS AND RESULTS In this randomised, placebo-controlled, double-blinded, single-centre trial, we enrolled patients with severe aortic stenosis and iron deficiency (defined as ferritin < 100 μg/L, or 100-299 μg/L with a transferrin saturation < 20 %) who were evaluated for TAVI. Patients were randomly assigned (1:1) to receive i.v. ferric derisomaltose or placebo approximately three months before TAVI. The primary endpoint was the between-group, baseline-adjusted six-minute walk distance measured three months after TAVI. Secondary outcomes included quality of life, iron stores, handgrip strength, NYHA class, and safety. Between January 2020 and September 2021, we randomised 74 patients to ferric derisomaltose and 75 patients to placebo. The modified intention-to-treat population comprised the 104 patients who completed the six-minute walk test at baseline and three months after successful TAVI. Iron stores were restored in 76 % of the patients allocated to iron and 13 % of the patients allocated to placebo (p < 0.001). There was no difference in the baseline-adjusted six-minute walk distance between the two treatment arms (p = 0.82). The number of serious adverse events, quality of life, handgrip strength, and NYHA class did not differ between the treatment arms. CONCLUSION Treatment with intravenous iron did not provide clinical benefit beyond TAVI in iron deficient patients with severe aortic stenosis.
Effects of ferric carboxymaltose on hemoglobin level after cardiac surgery: A randomized controlled trial
Anaesthesia, critical care & pain medicine. 2022;:101171
BACKGROUND Perioperative anemia is common in cardiac surgery. Few studies investigated the effect of postoperative intravenous (IV) iron supplementation and were mostly inconclusive. METHODS Design: A randomized single-center, double-blind, placebo-controlled, parallel-group trial. PARTICIPANTS 195 non-anemic patients were recruited from December 2018 until December 2020: 97 patients received 1 g of ferric carboxymaltose (FCM) and 98 patients received 100 mL of physiological serum on postoperative day 1. MEASUREMENTS hemoglobin levels, reticulocyte count, serum iron, serum ferritin, and transferrin saturation were measured at induction of anesthesia, postoperative days 1, 5, and 30. Transfusion rate, duration of mechanical ventilation, critical care unit length of stay, and side effects associated with IV iron administration were measured. The primary outcome was hemoglobin level on day 30. Secondary outcomes included iron balance, transfused red cell packs, and critical care unit length of stay. RESULTS At day 30, the hemoglobine level was higher in the FCM group than in the placebo group (mean 12.9 ± 1.2 vs. 12.1 ± 1.3 g/dL, 95%CI 0.41-1.23, p-value <0.001). Patients in the FCM group received fewer blood units (median 1[0-2] unit vs. 2 [0-3] units, p-value = 0.037) and had significant improvement in iron balance compared to the control group. No side effects associated with FCM administration were reported. CONCLUSION In this randomized controlled trial, administration of FCM on postoperative day 1 in non-anemic patients undergoing cardiac surgery increased hemoglobin levels by 0.8 g/dL on postoperative day 30, leading to reduced transfusion rate, and improved iron levels on postoperative day 5 and 30 (NCT03759964). CLINICAL TRIAL REGISTRY NUMBER NCT03759964.
Intravenous iron supplementation treats anemia and reduces blood transfusion requirements in patients undergoing coronary artery bypass grafting-A prospective randomized trial
Annals of cardiac anaesthesia. 2022;25(2):141-147
STUDY OBJECTIVE Preoperative anemia results in two- to sixfold increased incidence of perioperative blood transfusion requirements and reduced postoperative hemoglobin (Hb) level. This prospective study was designed to investigate the effect of preoperative intravenous infusion of iron on Hb levels, blood transfusion requirements, and incidence of postoperative adverse events in patients undergoing coronary artery bypass grafting. DESIGN Prospective randomized trial. SETTING Academic university hospital. PATIENTS Eighty patients (52-67 years old) underwent coronary artery bypass grafting and received either iron therapy or saline infusion preoperatively. INTERVENTIONS Patients were randomly allocated to iron or placebo groups. In the iron group, patients received a single intravenous dose of ferric carboxymaltose (1000 mg in 100 mL saline) infused slowly over 15 min 7 days before surgery. In placebo group, patients received a single intravenous dose of saline (100 mL saline) infused slowly over 15 min 7 days before surgery. MEASUREMENTS Patients were followed up with regards to incidence of anemia, Hb level on admission, preoperatively, postoperatively, 1 week and 4 weeks after discharge, aortic cross-clamp time, the number of packed red blood cells (pRBCs) units, the percentage of reticulocytes pre-postoperatively and 1 week later, hospital stay and intensive care unit (ICU) stay length, and the incidence of postoperative complications. MAIN RESULTS Iron therapy was associated with lower incidence of anemia 4 weeks after discharge (P < 0.001). Hb level was significantly higher in the iron group compared to the placebo group preoperatively and postoperatively, and 4 weeks after discharge (P < 0.001). Iron therapy resulted in shorter hospital and ICU stay (P < 0.001) and shorter aortic cross-clamp time, reduced pRBCs requirements postoperatively. Percentage of reticulocytes was significantly higher in placebo group than in iron group postoperatively and 1 week after discharge and the incidence of postoperative complications was similar to the placebo group. CONCLUSIONS Preoperative IV iron infusion is a safe and feasible way to manage preoperative anemia. Preoperative administration of IV iron is associated with a higher postoperative Hb level, shorter hospital and ICU stay, and reduced perioperative red blood cell transfusion requirements with insignificant difference in incidence of postoperative complications.
Iron supplementation for patients undergoing cardiac surgery: a systematic review and meta-analysis of randomized controlled trials
Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2021
PURPOSE Iron supplementation has been evaluated in several randomized controlled trials (RCTs) for its potential to increase baseline hemoglobin and decrease red blood cell transfusion during cardiac surgery. This study's main objective was to evaluate the current evidence for iron administration in cardiac surgery patients. METHODS We searched MEDLINE, EMBASE, CENTRAL, Web of Science databases, and Google Scholar from inception to 19 November 2020 for RCTs evaluating perioperative iron administration in adult patients undergoing cardiac surgery. The RCTs were assessed using a risk of bias assessment and the quality of evidence was assessed using the grading of recommendations, assessments, development, and evaluations. RESULTS We reviewed 1,767 citations, and five studies (n = 554) met the inclusion criteria. The use of iron showed no statistical difference in incidence of transfusion (risk ratio, 0.86; 95% confidence interval, 0.65 to 1.13). Trial sequential analysis suggested an optimal information size of 1,132 participants, which the accrued information size did not reach. CONCLUSION The current literature does not support or refute the routine use of iron therapy in cardiac surgery patients. TRIAL REGISTRATION PROSPERO (CRD42020161927); registered 19 December 2019.
Patients undergoing cardiac surgery (5 studies, n= 554).
Placebo, or no-treatment.
Based on the pooling of data from four trials (n= 449), the use of iron showed no statistical difference in the incidence of transfusion (RR, 0.86). There was low heterogeneity between studies (I2 = 0%). One trial (n= 60) reported a significant decrease in the number of red blood cells transfused (mean differences, -1.0 units). All five trials (n= 554) showed no difference in serious adverse events using iron therapy (risk difference, 0.0).
The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial
European heart journal. 2021
AIMS: Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF. METHODS AND RESULTS Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force-frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (-0.23%, 95% CI -1.44%; +0.97%; P < 0.001). Similarly, LVESV (-9.72 mL, 95% CI -13.5 mL; -5.93 mL vs. -1.83 mL, 95% CI -5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force-frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force-frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM. CONCLUSIONS Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force-frequency relationship.
Intravenous iron supplement for iron deficiency in cardiac transplant recipients (IronIC): A randomized clinical trial
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2021
AIMS: Heart transplant recipients have reduced exercise capacity despite preserved graft function. The IronIC trial was designed to test the hypothesis that intravenous iron therapy would improve peak oxygen consumption in these patients. METHODS AND RESULTS This randomized, placebo-controlled, double-blind trial was performed at our national center for heart transplantation. One hundred and 2 heart transplant recipients with a serum ferritin <100 µg/liter or 100 to 300 µg/liter, in combination with transferrin saturation of <20%, and hemoglobin level >100 g/liter were enrolled ≥1 year after transplantation. A cardiopulmonary exercise test was performed before administration of the study drug and at 6 months follow-up. The primary endpoint was peak oxygen consumption. Key secondary outcomes included iron status, handgrip strength, quality of life, and safety. Fifty-two patients were randomized to receive ferric derisomaltose 20 mg/kg, and 50 to placebo. The between-group difference in baseline-adjusted peak oxygen consumption was 0.3 ml/kg/min (95% confidence interval -0.9 to 1.4, p = 0.66). In patients with a baseline ferritin <30 µg/liter, peak oxygen consumption was significantly higher in the ferric derisomaltose arm. At 6 months, iron stores were restored in 86% of the patients receiving ferric derisomaltose vs 20% in patients receiving placebo (p < 0.001). Quality of life was significantly better in patients receiving ferric derisomaltose. Twenty-seven adverse events occurred in the intravenous iron group vs 30 in the placebo group (p = 0.39). CONCLUSION Intravenous iron treatment did not improve peak oxygen consumption in heart transplant recipients with ferritin <100 µg/liter or 100 to 300 µg/liter in combination with transferrin saturation <20%. TRIAL REGISTRATION NUMBER http//www.clinicaltrials.gov identifier NCT03662789.
Preoperative Sucrosomial Iron Supplementation Increases Haemoglobin and Reduces Transfusion Requirements in Elective Heart Surgery Patients: A Prospective Randomized Study
Surgical technology international. 2021;39
BACKGROUND Low preoperative haemoglobin is frequently observed in heart surgery patients and is associated with a significant decrease in haemoglobin between post-operative days 2 and 3, known as haemoglobin drift. Overall, these patients tend to receive many RBC transfusions. Since iron homeostasis is often impaired in these patients, restoration of iron availability might override iron-restricted erythropoiesis. However, reduced tolerance to oral iron salts has limited this strategy to intravenous iron administration. STUDY DESIGN AND METHODS The purpose of this study was to assess whether preoperative supplementation with oral sucrosomial iron, a new iron-delivery technology with improved tolerance and bioavailability, might be an effective strategy for this patient population. One thousand consecutive patients were randomized and received either a one-month course of sucrosomial iron (60 mg/day) or no treatment prior to elective heart surgery at a single high-volume centre (ClinicalTrials.gov NCT03560687). Primary end-points were haemoglobin concentration on the day of hospital admittance and number of blood transfusions. Secondary end-points were haemoglobin drift, tolerance of treatment and cost-effectiveness of sucrosomial iron administration. RESULTS Baseline haemoglobin in the treatment group was higher (by 0.67 g/dL; p<0.001) than that in the control group. The percentage of patients in the treatment group who required transfusion (35.4%) was half that in the control group (64.6%). The average number of transfused units per operation was 0.95 vs. 2.03 in the treatment and control groups, respectively. Haemoglobin drift was substantially similar in the two groups, and the tolerability of treatment was excellent (98%). The overall cost of treatment was 156 Euros less in the treatment group, expressed as a raw cost of transfusion. CONCLUSION In elective heart surgery, routine preoperative sucrosomial iron administration seems to be a safe, well-tolerated and cost-effective strategy to increase preoperative haemoglobin and reduce the need for allogeneic blood transfusions.
Intravenous iron therapy for patients with preoperative iron deficiency or anaemia undergoing cardiac surgery reduces blood transfusions: a systematic review and meta-analysis
Interact Cardiovasc Thorac Surg. 2020
OBJECTIVES The benefits of preoperative intravenous (IV) iron treatment in cardiac surgery patients with preoperative anaemia or iron deficiency have not been well-established. We performed a systematic review and meta-analysis to determine the effects of treating preoperative anaemia or iron deficiency with IV iron in adult cardiac surgery patients. METHODS We searched Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval Systems Online and Excerpta Medica Database for randomized controlled trials (RCTs) and observational studies comparing IV iron to oral iron or no iron. We performed title and abstract, full-text screening, data extraction and risk of bias assessment independently and in duplicate. We pooled data using a random effects model and evaluated the overall quality of evidence. RESULTS We identified 4 RCTs and 7 observational studies. Pooled data from observational studies suggested a benefit of IV iron compared to no iron on mortality [relative risk 0.39, 95% confidence interval (CI) 0.23-0.65; P < 0.001, very low quality], units transfused per patient (mean difference -1.22, 95% CI -1.85 to -0.60; P < 0.001, very low quality), renal injury (relative risk 0.50, 95% CI 0.36-0.69; P < 0.001, very low quality) and hospital length of stay (mean difference -4.24 days, 95% CI -6.86 to -1.63; P = 0.001, very low quality). Pooled data from RCTs demonstrated a reduction in the number of patients transfused with IV iron compared to oral or no iron (relative risk 0.81, 95% CI 0.70-0.94; P = 0.005, moderate quality). The pooled estimates of effect from RCTs for mortality, hospital length of stay, units transfused per patient and renal injury were consistent in direction with observational studies. CONCLUSIONS This meta-analysis suggests that IV iron improves postoperative morbidity in adult cardiac surgery patients with preoperative anaemia or iron deficiency. A large, rigorous, placebo-controlled, double-blinded, multicentre trial is needed to clarify the role of IV iron in this patient population. CLINICAL TRIAL REGISTRATION International prospective register of systematic reviews ID Number CRD42019122844.
Adult cardiac surgery patients with preoperative anaemia or iron deficiency (11 studies, n= 1657).
Intravenous (IV) iron treatment.
Oral iron or no iron.
Pooled data from observational studies suggested a benefit of IV iron compared to no iron on mortality, units transfused per patient, renal injury and hospital length of stay. Pooled data from randomised controlled trials (RCTs) demonstrated a reduction in the number of patients transfused with IV iron compared to oral or no iron. The pooled estimates of effect from RCTs for mortality, hospital length of stay, units transfused per patient and renal injury were consistent in direction with observational studies.