High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.
Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.
Intravenous iron repletion produces consistent clinical benefit in symptomatic HF patients with reduced left ventricular ejection fraction (LVEF) who also have iron deficiency. But repeated IV treatments are impractical for many patients, and clinicians have turned to prescribing oral iron supplements in the hope of achieving similar results. However, until now, no large randomized, controlled clinical trials have examined the effectiveness of the oral route of administration, Dr. Lewis and his associates noted.
The IRONOUT study was conducted at 23 U.S. medical centers, where outcomes after 16 weeks of oral iron therapy (150 mg twice daily) were compared against matching placebo in 225 patients. The median patient age was 63 years, and the median duration of HF was 5.7 years. Ischemic heart disease was the primary cause of HF in 78% of the study participants.
These patients had low LVEF and poor exercise capacity, despite having high rates of guideline-directed treatment with medications.
The primary endpoint was a change in peak oxygen uptake (peak VO2) at the conclusion of treatment, a measure that “reflects the multiple mechanisms by which iron repletion is expected to improve systemic oxygen delivery and utilization.” Change in peak VO2 was not significantly different between the 111 participants who took oral iron supplements (+23 mL/min) and the 114 who took placebo (–2 mL/min), the investigators wrote (JAMA Pediatr. 2017 May 16. doi: 10.1001/jama.2017.5427).
In subgroup analyses, oral iron also failed to improve peak VO2 in any subgroup of patients: neither men nor women; neither those with decreased hemoglobin nor those with normal hemoglobin levels; nor patients with or without venous congestion at baseline. Oral iron also failed to improve secondary endpoints including 6-minute walk distance, quality of life scores, NT-proBNP levels, and ventilatory efficiency.
In contrast to previous studies of IV iron repletion, oral iron supplementation “produced minimal improvement in iron stores, implicating the route of administration rather than the strategy of iron repletion in the lack of clinical benefit,” Dr. Lewis and his associates said.
This study was funded by the National Heart, Lung, and Blood Institute, which also conceived, designed, and conducted the trial. Dr. Lewis reported ties to Abbott, Novartis, Shape Systems, Stealth Bio Therapeutics, Ironwood, Cheetah Medical, Luitpold, and SoniVie. His associates reported ties to numerous industry sources.
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