Exercise Capacity in Heart Failure With Reduced Ejection Fraction Not Improved With Iron Supplementation

In a recent study published in JAMA, oral iron supplementation did not improve exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency.¹

An estimated 50% of patients with HFrEF have iron deficiency, which is linked to increased mortality and reduced quality of life and functional capacity in these individuals.^2,3

“[C]ells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” the study authors noted. “Cardiac iron deficiency is present in patients with heart failure and associated with impaired mitochondrial function, abnormal sarcomere structure, and left ventricular systolic dysfunction.”

Although intravenous iron repletion has been found to improve outcomes in such patients, this approach is cost-prohibitive and may be inconvenient for outpatients.^4,5

The current trial investigated the effects of oral iron supplementation on exercise capacity in patients with HFrEF and iron deficiency (median age, 63 years; 36% women). One group (n=111) of patients received oral iron polysaccharide 150 mg twice daily for 16 weeks, whereas the other group (n=114) received a placebo.

There was no significant difference between groups in the primary end point of change in peak oxygen uptake (Vo₂; +23 mL/min vs −2 mL/min; 95% CI, −34 to +76 mL/min; P =.46) or in the secondary end points: changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (159 pg/mL; 95% CI, −280 to 599 pg/mL), or quality of life as indicated by scores on the Kansas City Cardiomyopathy Questionnaire (1; 95% CI, −2.4 to 4.4), all P >.05.

The iron group showed only a minor increase in iron repletion vs placebo: transferrin saturation [Tsat] levels (+3.3%; 95% CI, 1.1%-5.4%; P=.003) and ferritin levels (+11.3 ng/mL; 95% CI, 0.3-22.9 ng/mL; P =.06)

These results conflict with those pertaining to intravenous iron repletion, in which the median increase in Tsat and ferritin was 70% and 550%, respectively.⁴ This suggests that the route of administration may be a key factor in the effectiveness of iron supplementation. In addition, reduced iron repletion in the present research was observed in patients with higher baseline hepcidin, a peptide that limits iron absorption, which points to the possibility that elevated hepcidin may have inhibited patients’ responsiveness to oral iron.

“This study’s findings of minimal changes in iron stores and lack of effect on peak exercise capacity suggests that prescription of oral iron in patients with HFrEF offers no benefit,” the researchers concluded.

References

1. Lewis GD, Malhotra R, Hernandez AF, et al; NHLBI Heart Failure Clinical Research Network. 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

2. Klip IT, Comin-Colet , Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(4):575-582. doi:10.1016/j.ahj.2013.01.017

3. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011;17(11):899-906. doi:10.1016/j.cardfail.2011.08.003

4. Anker SD, Comin Colet J, Filippatos G, et al; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448. doi:10.1056/NEJMoa0908355

5. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657-668. doi:10.1093/eurheartj/ehu385