1. Oral iron repletion did not improve exercise capacity as measured by peak oxygen uptake (VO2).
2. There were no significant effects from oral iron repletion on 6-minute walk distance, NT-proBNP levels, or overall health status.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Iron is a major component of hemoglobin and plays a critical role in systemic oxygen delivery and cellular respiration in the human body. Iron deficiency affects one-half of all patients with heart failure and significantly reduces the oxygen carrying capacity of the blood. Cardiac muscle cells have high energy demands and are especially susceptible to iron deficiency. While maintaining adequate iron levels is thought to be an important part of heart failure care, no randomized clinical trials (RCT) have been conducted to study the effects of oral iron repletion.
The present study is a phase 2, double-blind, placebo-controlled RCT that investigates the role of oral iron repletion in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency. Among 225 participants (median age, 63.0 years; 36% women, 25% average left ventricular ejection fraction), the change in peak oxygen uptake (VO2) from baseline to 16 weeks did not differ significantly between the oral iron and placebo groups(difference 21 mL/min; p = 0.46). There were no between-group differences in 6-minute walk distance, NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire (KCCQ), O2 uptake kinetics, or ventilatory efficiency (all p > 0.5).
Overall, the results suggest supplementation of high-dose oral iron repletion in patients with HFrEF and iron deficiency may be of limited effectiveness. Limitations of this study include its short duration of follow-up, its lack of comparison between oral and intravenous iron repletion, and its potentially limited generalizability. Future directions should include studying longer term effects of iron repletion, as well as other modes of treating iron deficiency or improving oxygen carrying capacity in patients with heart failure.
In-Depth [randomized clinical trial]: Clinically stable patients receiving medical therapy for reduced left ventricular ejection fraction (less than or equal to 40%) and heart failure (NYHA II-IV) were eligible for this study if they presented with objective standards of iron deficiency. Participants that met screening criteria underwent tests including cardiopulmonary exercise testing, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), phlebotomy for biomarkers, and were randomly assigned in a 1-to-1 ratio to receive either oral iron polysaccharide or placebo. Intervention patients were administered drug orally at 150 mg, twice daily for 16 weeks. At 8 and 16 weeks, all baseline tests were repeated. The primary end point was the change in peak oxygen flow (peak VO2) after 16 weeks of therapy, while secondary end points included suboptimal exercise capacity, ventilator efficiency, 6-minute walk distance, plasma N-terminal pro-BNP, and KCCQ.
Across 23 sites in the United States, a total of 225 participants were enrolled in the study from September 3, 2014 to November 18, 2015. Patient cohort characteristics included a median age of 63 years, 36% women, 5.7 years median duration of heart failure, 78% participants with ischemic heart disease etiology, 1111 pg/mL median NT-proBNP at enrollment, 25% median left ventricular ejection fraction, and 13.2 mL/kg/min median peak VO2 (low). Patients also had low ferritin levels (median 69 ng/mL), low transferrin saturation (median 18%), low hemoglobin levels (median 12.6 g/dL), elevated soluble transferrin receptors (median 3.8 mg/L), and elevated hepcidin (median 7.0 ng/mL). Median baseline peak VO2 was 1196 mL/min (IQR, 887 to 1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887 to 1449 mL/min) in the placebo group. Change in peak VO2 did not differ between the two groups (+23 mL/min for oral iron vs +2 mL/min for placebo) with a between group difference of 21 mL/min (p = 0.46). Similarly, no significant differences between treatment groups were found with 6-minute walk distance, NT-proBNP levels, KCCQ score, O2 uptake kinetics, or ventilator efficiency. Median hepcidin levels increased in the oral iron group (6.7 to 8.9 ng/mL; p = 0.007) and remained unchanged in the placebo group (7.4 to 7.8 ng/mL; p = 0.91) with a between group comparison that was not significant.
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