Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency

Abstract

Importance Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive, readily available oral iron supplementation in heart failure is unknown. Objective To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. Design, Setting, and Participants Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as serum ferritin level between 15–100 ng/ml or serum ferritin 101-299 ng/ml with transferrin saturation (Tsat) <20%. Patients were enrolled between September 2014 and November 2015 at 23 US sites. Interventions Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. Main Outcomes and Measures The primary endpoint was a change in peak oxygen uptake (VO2), from baseline to 16 weeks. Secondary endpoints included changes in six minute walk distance; plasma NT-pro BNP levels; and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). Results Among 225 randomized patients (median age 63 years, 36% women) 203 completed the study. The median baseline peak VO2 was 1196 ml/min (887, 1448 ml/min) in the oral iron group and 1167 ml/min (887, 1449 ml/min) in the placebo group. The primary endpoint, change in peak VO2, did not significantly differ between the oral iron and placebo groups (+23 ml/min vs −2 ml/min; difference, 21 ml/min [95% CI, −34 to +76]; P=.46). Similarly, at 16 weeks there were no significant differences between treatment groups in changes in 6-minute walk distance (−13, −32 to 6m), NT-pro BNP levels (159, −280 to 599 pg/ml), KCCQ Score (1, −2.4 to 4.4) or time to first adverse event (hazard ratio 0.85, 0.56 to 1.31), all p>0.05. Conclusion Among patients with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF.

Modern iron replacement therapy: clinical and pathophysiological insights

“…Noteworthy, a sub-analysis of the seminal FAIR-HF trial [74] focusing on anemic CHF patients showed consistent Hb increase after IV iron, implicitly validating the above mentioned "extensive" criteria for ID [128]. As mentioned above, the beneficial effect of iron in CHF is seen only using IV preparation (for now FCM is the only compound tested in such condition), while a recent trial with oral iron was unsuccessful because of increased hepcidin levels [76]. As depicted in Fig.…”

“…This results in decreased utilization of O 2 by irondependent mitochondrial enzymes in cardiomyocytes [72], and an increased risk of hospitalization or even of death [70,73]. Of note, IV iron therapy has been shown to be beneficial in CHF patients with ID (see also below) [71,74,75], while a recent trial with oral iron yielded negative results [76]. This refractoriness to oral iron was linked to relatively high (instead of suppressed) hepcidin levels in CHF ID patients [76].…”

“…Of note, IV iron therapy has been shown to be beneficial in CHF patients with ID (see also below) [71,74,75], while a recent trial with oral iron yielded negative results [76]. This refractoriness to oral iron was linked to relatively high (instead of suppressed) hepcidin levels in CHF ID patients [76]. Thus, CHF represents a paradigmatic condition where recent pathophysiological insights on hepcidin appear to influence the choice on the most appropriate route of iron administration.…”

Niedokrwistość i niedobór żelaza u chorych z niewydolnością serca — postępowanie diagnostyczne i terapeutyczne

“…Ich rolą jest wyłapywanie i internalizacja transferryny w celu pozyskania żelaza przez komórki docelowe, podczas gdy rolą ferrytyny jest przechowywanie żelaza w tkankach (ryc. 3) [28,29].…”

The problem of anemia treatment in patients with chronic heart failure.

“…При інфекційних процесах залізо гальмує фагоцитарну активність нейтро-філів і стимулює проліферацію мікробних аген-тів, хоча це застереження підтримують не всі дослідники. Більшість авторів надають перевагу застосуванню парентерального заліза в пацієнтів з АХЗ [26,30].…”