Heart Failure Network (HFN) Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT)
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Open BioLINCC Study See bottom of this webpage for request information
September 2014 – April 2016
Dataset(s) Last Updated
March 11, 2022
Clinical Trial URLs
Primary Publication URLs
Commercial Use Data Restrictions No
Data Restrictions Based On Area Of Research No
To test the hypothesis that, compared to placebo, oral iron repletion in heart failure patients with iron deficiency improves exercise capacity after 16 weeks of therapy.
Iron deficiency affects approximately one half of patients with symptomatic heart failure. The presence of iron deficiency in patients with heart failure is associated with reduced functional capacity, poorer quality of life, and increased mortality.
Despite growing recognition of the significance of iron deficiency, randomized multicenter trials exploring the utility of oral iron supplementation, a therapy that is inexpensive, readily available, and safe, have not been performed in patients with heart failure. Moreover, patient characteristics and biochemical profiles that may influence responsiveness to oral iron in patients with heart failure have not been defined. Results of intravenous iron repletion trials have been favorable, but regularly treating patients with intravenous iron products is expensive and poses logistical challenges for outpatients. Therefore, the HFN-IRONOUT study was initiated to investigate the efficacy of oral iron in patients with heart failure with reduced ejection fraction (HFrEF).
Patients with reduced left ventricular ejection fraction (≤40%) and heart failure with New York Heart Association functional class II through IV symptoms who were stable while receiving medical therapy were eligible to participate if they had objective evidence of iron deficiency (ferritin 15-100 ng/ml or between 100-299 ng/ml with a transferrin saturation [Tsat] below 20%) and hemoglobin levels between 9-15 g/dl (males) or 9-13.5 g/dl (females).
A total of 225 patients were enrolled, 111 randomized to receive oral iron and 114 randomized to receive the placebo.
The HFN-IRONOUT study was a phase 2, double-blind, placebo-controlled randomized clinical trial that enrolled patients at 23 sites in the United States. Patients were randomly assigned, in a 1:1 ratio, to receive either oral iron polysaccharide or placebo with the use of an automated web-based system. A permuted block randomization method (with 4 participants per block) was stratified by enrolling site and anemia status (defined as hemoglobin < 12 g/dL). Study drug was administered orally at 150 mg, twice daily for 16 weeks.
At baseline, 8 weeks, and 16 weeks patients underwent studies including history and physical examination, cardiopulmonary exercise testing (CPET), Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk test. CPETs were performed using a 10 Watt/minute incremental ramp protocol and breath-by-breath measures of oxygen uptake were uniformly analyzed by the CPET Core Lab. Patients also underwent phlebotomy for biomarkers. Iron studies, including iron, total iron binding capacity, and ferritin, were measured at baseline and after 16 weeks to determine the extent to which oral iron led to iron repletion.
The primary end point was the change in peak oxygen uptake (peak VO2) after 16 weeks of therapy.
Among patients with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks.
Lewis GD, Malhotra R, Hernandez A, et al. Effect of Oral Iron Repletion on Exercise Capacity in Patients with Heart Failure with Reduced Ejection Fraction and Iron Deficiency: the IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427
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Resources AvailableStudy Datasets Only
- Data Dictionary (PDF - 1.5 MB)
- HFN IRONOUT Cardiopulmonary Exercise Testing Manual of Operating Procedures (PDF - 1.5 MB)
- HFN IRONOUT Case Report Forms (PDF - 8.2 MB)
- HFN IRONOUT Manual of Operations (PDF - 600.6 KB)
- HFN IRONOUT Protocol (PDF - 1.4 MB)
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