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

May 2017

DOI: 10.1001/jama.2017.5427

Citations:406

Influential Citations:9

Interventional (Human) Studies

High RoB

COI

Enhanced Details

Methods

Multicenter, randomized, double-blind, placebo-controlled trial in 225 adults with heart failure with reduced ejection fraction (EF ≤40%), NYHA class II–IV, iron deficiency defined by ferritin 15–100 ng/mL or ferritin 100–299 ng/mL with TSAT <20%; Hb 9–15 g/dL (men) or 9–13.5 g/dL (women); median age 63 years, 36% female; stable on guideline-directed medical therapy; enrolled at 23 sites.

Intervention

Oral iron polysaccharide, 150 mg, twice daily, for 16 weeks.

Results

Primary endpoint (change in peak VO2 after 16 weeks) did not differ between groups (oral iron +23 ml/min vs placebo -2 ml/min; between-group difference 21 ml/min, 95% CI −34 to 76; P = 0.46). No significant differences in secondary endpoints (6-minute walk distance, NT-proBNP, KCCQ, O2 uptake kinetics, VE/VCO2 slope). Iron indices improved modestly with oral iron (Tsat +3 percentage points; ferritin +11 ng/mL; soluble transferrin receptor −0.3 mg/L; P = .003 for Tsat; P = .06 for ferritin; P = .01 for sTfR). Higher baseline Tsat correlated with better exercise capacity; baseline hepcidin rose with oral iron and predicted poorer iron repletion. Conclusion: high-dose oral iron minimally increases iron stores and does not improve exercise capacity; does not support use of oral iron in iron-deficient HFrEF.

Limitations

Not powered for clinical events or safety endpoints; no direct comparison with intravenous iron; relatively short duration (16 weeks); possible limited iron absorption due to hepcidin; findings may not generalize to HF with preserved ejection fraction.

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 a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants 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 end point was a change in peak oxygen uptake (V[Combining Dot Above]O2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) 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 participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V[Combining Dot Above]O2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V[Combining Dot Above]O2 at 16 weeks, 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 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), NT-proBNP levels (159; 95% CI, −280 to 599 pg/mL), or KCCQ score (1; 95% CI, −2.4 to 4.4), all P > .05. Conclusions and Relevance Among participants 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. Trial Registration clinicaltrials.gov Identifier: NCT02188784 show less