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Lewis GD, et al. "Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency". JAMA. 2017. 317(19):1958-66.
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Clinical Question

In patients with iron deficiency and symptomatic heart failure with reduced ejection fraction (HFrEF), does oral iron replacement improve exercise capacity?

Bottom Line

In patients with iron deficiency (ferritin 15-100 or 100-299 with transferrin saturation < 20%) and symptomatic HFrEF (LVEF ≤ 40% with NYHA II-IV), oral iron replacement had no effect on exercise capacity as measured using change in peak oxygen uptake (VO2).

Major Points

Iron plays a critical role in oxygen delivery by contributing to the production of red blood cells and serving as a cofactor for enzymes required to perform cellular respiration and maintain vascular homeostasis. Nearly 50% of patients with symptomatic HFrEF have iron deficiency which may impair these processes and prevent adequate compensation for impaired cardiac function. This notion is supported by the finding that regardless of hemoglobin status, the presence of iron deficiency in HFrEF has been associated with reduced functional capacity, poorer quality of life, and increased mortality.[1] Furthermore, in the FAIR-HF trial, patients with symptomatic HFrEF and iron deficiency (with or without anemia) given IV iron replacement had improvements in functional capacity, heart failure symptoms, and quality of life. Whether these benefits would extend to the use of inexpensive and readily available oral iron replacement remained unknown.

The 2017 Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial randomized 225 patients with symptomatic HFrEF (LVEF < 40% with NYHA II-IV symptoms) and iron deficiency (either ferritin 15-100ng/mL or 100-299 ng/ML with TSat < 20%) to either oral iron polysaccharide (150MG twice daily) or placebo and assessed for a primary outcome of change in exercise capacity as measured by increase in peak oxygen uptake (VO2 max) on cardiopulmonary exercise testing (CPET). At 16 weeks, change in VO2 max was similar in both groups, with little change from baseline. There was also no change in secondary outcomes including 6-minute walk distance, NTproBNP levels, or quality of life. Importantly, iron markers were only modestly improved with oral iron therapy in IRONOUT-HF, suggesting that the route of administration is likely to blame for the lack of response rather than the overall strategy of increasing iron stores.

In summary, the results of IRONOUT-HF suggest that there is currently no role for routine oral iron supplementation in patients with HFrEF and iron deficiency. Given what is known from FAIR-HF, most of these patients would be expected to derive benefit from IV iron in the absence of contraindications.


As of June 2017, no guidelines have been published that reflect the results of this trial.


  • Prospective, multi-center, double-blind, randomized controlled trial
  • N=225
    • Iron polysaccharide (n=111)
    • Placebo (n=114)
  • Setting: 23 sites in the US
  • Enrollment: September 3, 2014 through November 18, 2015
  • Duration follow-up: 16 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Change in peak oxygen uptake on CPET (peak VO2)


Inclusion Criteria

  • Age ≥ 18 years
  • Previous clinical diagnosis of heart failure with current NYHA class II-IV symptoms, LVEF ≤ 40% within 2 years, and ≥ 3 months after a major change in cardiac status (i.e., CABG or CRT)
  • Serum ferritin 15-100 ng/mL or 100-299 ng/mL with transferrin saturation < 20%
  • Hemoglobin 9.0-15.0 g/dL (males), 9.0-13.5 (females)
  • Evidence-based therapy for HF (including beta blocker and ACE inhibitor/ARB unless previously deemed intolerant and diuretics as necessary) with ≤ 100% change in dose 30 days prior to randomization

Exclusion Criteria

  • Presence of a neuromuscular, orthopedic, or other non-cardiac condition that prevents the patient from exercise testing or prevents ability to achieve an RER ≥ 1.0 on screening/baseline CPET
  • GFR < 20mL/min/1.73m2
  • ALT or AST > 3x normal, AP or bilirubin > 2x normal
  • GI conditions known to impair iron absorption
  • Known active infection as defined by current use of oral of IV antimicrobial agents
  • Active GI bleeding
  • Active malignancy (other than non-melanoma skin cancer)
  • Anemia with known cause other than iron deficiency or chronic disease
  • Iron overload disorders
  • History of erythropoeitin, IV or oral iron therapy, or blood transfusion in the previous 3 months
  • Current ventricular assist device
  • Anticipated cardiac transplantation within the next 4 months
  • Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis, or tamponade
  • Previous adverse reaction to study drug or other oral iron repletion
  • Known or anticipated pregnancy in the next 4 months

Baseline Characteristics

All patients

  • Demographics: age 63, female 36%, BMI 29.2
  • CHF: LVEF 25%, NYHA II 67%, NYHA III 33%, KCCQ 71.9, 6-minute walk 363m, CHF hospitalization within past year 43%
  • Co-morbidities: CAD 78%, HTN 72%, AF 39%, DM 39%, CKD 23%
  • Medications: Beta blocker 96%, ACE/ARB 84%, loop diuretic 83%, antiplatelet 68%, aldosterone antagonist 60%, anticoagulant 46%, digoxin 22%, nitrate 20%, hydralazine 15%
  • Labs: Cr 1.2, NTproBNP 1111, hgb 12.6, iron 62, TIBC 349, ferritin 69, tsat 18%, hepcidin 7
  • CPET: peak VO2 1172 mL/min, peak RER 1.1, VE/VCO2 slope 34, ventilatory threshold 695 mL/min


  • Randomized 1:1 to oral iron polysaccharide 150MG twice daily or matching placebo
    • Randomization performed in permuted blocks stratified by enrolling site and anemia status (defined as hgb < 12)
  • Patients underwent baseline screening measurements including history and physical examination, CPET, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-minute walk test, and biomarker testing
  • Baseline and follow-up CPET performed using 10W/min incremental ramp protocol
  • Study drug administered for 16 weeks
  • Follow-up history and physical examination, CPET, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-minute walk test, and biomarker testing performed at the end of 16 weeks


Comparisons are oral iron vs. placebo

Primary Outcomes

Peak VO2 (16 weeks)
1218 (95% CI 892 to 1500) vs. 1187 (95% CI 902 to 1425) [p=0.46]
Peak VO2 (16 weeks, change from baseline)
23 (95% CI -84 to 142) vs. -2 (95% CI -110 to 104) [p=0.46]

Secondary Outcomes

6-minute walk distance
366 (95% CI 315 to 456) vs. 397 (95% CI 299 to 472) [p=0.19]
889 (95% CI 376 to 2373) vs. 1085 (95% CI 447 to 2582) [p=0.48]
KCCQ clinical summary score
80.7 (95% CI 67.7 to 91.6) vs. 77.1 (95% CI 65.1 to 89.6) [p=0.57]
80 (95% CI 59 to 99) vs. 72 (95% CI 58 to 90) [p=0.009]
95 (95% CI 58 to 134) vs. 75 (95% CI 42 to 123) [p=0.06]

Subgroup Analysis

  • Change in peak VO2 was not significantly different between treatment groups in men vs. women, participants with or without hemoglobin level of less than 12 g/dL in women and of less than 13.5 g/dL in men, participants with or without baseline venous congestion, or participants with or without peak respiratory exchange ratios greater than 1.1 on baseline and 16-week CPETs

Adverse Events

Adverse events
39 (35%) vs. 45 (39%) [OR 0.83, 95% CI 0.48-1.43, p=0.50]
Serious adverse events
11 (10%) vs. 10 (9%) [OR 1.14, 95% CI 0.47-2.81, p=0.77]
Death or cardiovascular hospitalization
14 (13%) vs. 12 (11%) [OR 1.19, 95% CI 0.55-2.59, p=0.64]


  • Although peak VO2 is the gold standard for exercise capacity in CHF, this study was designed to assess for hard cardiovascular outcomes such as heart failure related death or morbidity.
  • Limited follow-up period of 16 weeks limits ability to detect a longer term benefit with oral iron therapy.


  • Authors with multiple ties to industry
  • NHLBI-sponsored trial

Further Reading