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1 Supplementary Online Content Lewis GD, Malhotra R, Hernandez AF, et al. 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. doi: /jama ebox. IRONOUT HF Inclusion and Exclusion Criteria etable 1. Serious Adverse Events Listed by Body System for the 2 Treatment Groups etable 2. Multicenter Trials That Evaluated Iron Supplementation for Treatment of Iron Deficiency in Patients With Heart Failure efigure 1. Forest Plot For Prespecified Subgroup Analysis Relative to the Primary End Point of Change in Peak VO2 at Week 16 efigure 2. Panel A: Time to First Serious and Nonserious Adverse Event Panel B: Time to Death or Cardiovascular Hospitalization ereferences This supplementary material has been provided by the authors to give readers additional information about their work.

2 ebox. IRONOUT HF Inclusion and Exclusion Criteria Inclusion Criteria 1. Age >18 years 2. Previous clinical diagnosis of heart failure with current NYHA Class II-IV symptoms, LVEF 0.40 within 2 years prior to consent, and 3 months after a major change in cardiac status (i.e. CABG or CRT). 3. Serum ferritin between ng/ml or serum ferritin between ng/ml with transferrin saturation <20% 4. Hemoglobin g/dl (males), (females) at time of enrollment 5. Evidence-based medical therapy for HF (including beta-blocker and ACEinhibitor/ARB unless previously deemed intolerant and diuretics as necessary) with 100% change in dose for 30 days prior to randomization. Changes in diuretic dose guided by a patient-directed flexible dosing program are considered stable medical therapy 6. Willingness to provide informed consent Exclusion Criteria 1. Presence of a neuromuscular, orthopedic or other non-cardiac condition that prevents the patient from exercise testing on a cycle/treadmill ergometer and/or inability to achieve an RER 1.0 on screening/baseline CPET 2. Severe renal dysfunction (egfr< 20 ml/min/1.73m 2 ) 3. Severe liver disease (ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal) 4. Gastrointestinal conditions known to impair Fe absorption (i.e. inflammatory bowel disease) 5. Known active infection as defined by current use of oral or intravenous antimicrobial agents 6. Documented active gastrointestinal bleeding 7. Active malignancy other than non-melanoma skin cancers 8. Anemia with known cause other than Iron deficiency or chronic disease 9. Iron overload disorders (i.e. hemochromatosis or hemosiderosis) 10. History of erythropoietin, IV or oral Fe therapy, or blood transfusion in previous 3 months. 11. Current ventricular assist device 12. Anticipated cardiac transplantation within the next 4 months 13. Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade 14. Previous adverse reaction to study drug or other oral Fe preparation 15. Known or anticipated pregnancy in the next 4 months

3 etable 1. Serious Adverse Events Listed by Body System for the 2 Treatment Groups Serious Adverse Event General Disorders And Administration Site Conditions Non-cardiac Chest Pain Gastrointestinal Disorders Abdominal Pain Gastrointestinal Pain Melena Rectal Hemorrhage Infections and Infestations Viral Bronchitis Viral Gastroenteritis Pneumonia Sepsis Streptococcal Sepsis Vestibular Neuronitis Injury, Poisoning And Procedural Complications Abdominal Injury Road Traffic Accident Investigations Liver Function Abnormal Norovirus Test Positive Metabolism and Nutrition Disorders Hyperosmolar Hyperglycemic State Musculoskeletal and Connective Tissue Disorders Musculoskeletal Chest Pain Rhabdomyolysis Neoplasms Benign Malignant and Unspecified (Including Cysts and Polyps) Skin Cancer Psychiatric Disorders Alcohol Withdrawal Syndrome Vascular Disorders Hypertensive Crisis Temporal Arteritis No. (%) of participants Oral Iron (N=111) 2 (2%) 2 (2%) 4 (4%) 4 (4%) 2 (2%) Placebo (N=11 4) 4 (4%) 3 (3%) 2 (2%) P-value

4 etable 2. Multicenter Trials That Evaluated Iron Supplementation for Treatment of Iron Deficiency in Patients With Heart Failure Drug IV Iron Sucrose Authors/ Journal Okonko 1 JACC 2008 N Patients Studied 35 NYHA 2-3 LVEF<0.35 Iron Deficiency Definition Ferritin<100 ng/ml or with Tsat<20% Study Duratio n 16 wks Primary Endpoint Peak VO 2 Changes in iron studies: iron-treated vs. placebo groups Ferritin: +273 ng/ml Tsat: +11% (both p<0.005) Major Findings Peak VO 2: +2.2 (0.5-4)ml/kg/min p=0.01 PGAS, NYHA IV Iron Carboxymaltose IV Iron Carboxymaltose Oral Iron Polysaccharide Anker 2 NEJM 2009 Ponikowsk i 3 EHJ NYHA 2-3 LVEF<0.4 Hb NYHA 2-3 LVEF<0.45 Hb <15 Lewis 225 NYHA 2-4 LVEF<0.40 Hb<13.5 (F) Hb<15 (M) Ferritin<100 ng/ml or with Tsat <20% Ferritin<100 ng/ml or with Tsat<20% Ferritin<100 ng/ml or with Tsat<20% 24 wks 52 wks 16 wks PGAS NYHA Ferritin: +238 ng/ml Tsat: +12% (both p<0.001) 6MWD Ferritin: +265 ng/ml Tsat: +9% (both p<0..001) Peak VO 2 Ferritin: +11 ng/ml p=0.056 Tsat: +3% p=0.003 PGAS (OR 2.5, ) NYHA (OR 2.4, ) 6MWD (+35m) Similar benefit for Hb<12 or >12 6MWD: +36 (13-57)m, p<0.001 PGAS, NYHA HF hospitalization (OR 0.39) Similar benefit for Hb<12 or >12 No significant change in peak VO 2, 6MWD, KCCQ, or NT- BNP Peak VO 2 : 21 (-34 to 76)ml/min Tsat, transferrin saturation; 6MWD, 6-minute walk distance; PGAS, patient global assessment score; NT-BNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association functional class; VO 2, oxygen consumption; Hb, hemoglobin; HF, heart failure; Tsat, transferrin saturation; KCCQ, Kansas City Cardiomyopathy Score. For major findings, values are provided for between group differences with 95% confidence intervals for the primary endpoints of the trials.

5 efigure 1. Forest Plot For Prespecified Subgroup Analysis Relative to the Primary End Point of Change in Peak VO 2 at Week 16

6 efigure 2. Panel A: Time to First Serious and Nonserious Adverse Event Panel B: Time to Death or Cardiovascular Hospitalization Panel A.

7 efigure 2. Panel B

8 References 1. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observerblinded trial. Journal of the American College of Cardiology. Jan ;51(2): Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. The New England journal of medicine. Dec ;361(25): Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. European heart journal. Mar ;36(11):