Heart Failure and Anemia

-Symptomatic heart failure at time of enrollment and for ≥ 3 months, in the opinion of the investigator -Exercise time at baseline, using the modified Naughton protocol, between 2 and 14 minutes for subjects ≤ 60 years of age and between 2 and 12 minutes for subjects > 60 years of age with a rating of perceived exertion (RPE) of at least 13 (“somewhat hard”) on the Borg scale. At least 2 screening exercise tests were required for enrollment of a subject. To establish reliability of exercise testing during screening, the result of the final screening exercise test must have been within 15% of the result of the preceding test. -Left ventricular ejection fraction (LVEF) ≤ 40% determined by generally accepted methods (eg, echocardiography, radionuclide ventriculography, ventricular angiography, or magnetic resonance imaging [MRI]) within 12 weeks before the week -1 visit. If no previous qualifying imaging study was available, ejection fraction for inclusion was determined by the local echocardiography assessment, performed before dosing (ie, the baseline echocardiography measurement) and before the echocardiographic tape was sent to the core echocardiogram laboratory -≥ 21 years old at time of signing the informed consent -Mean of the 2 screening hemoglobin concentrations (weeks -2 and -1) ≥ 9.0 g/dL and ≤ 12.5 g/dL (determined by central laboratory) -Transferrin saturation (TSAT) ≥ 15% (rounded to the nearest full percentage point) at the time of screening -Serum vitamin B12 and folate concentrations at or above the lower limit of the normal range at the time of screening -Treated for heart failure for at least 8 weeks (stable dose for the last 4 weeks) with an angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB), unless not tolerated. Beta-blocker was strongly suggested and, if taken, for at least 8 weeks at the time of expected randomization with stable dose for the last 4 weeks. Diuretics should have been used and adjusted as needed to maintain euvolemic state. Spironolactone and digoxin were optional. After a subject was randomized, changes in background therapy, except for diuretics, were discouraged.

-Poorly controlled hypertension, defined as blood pressure ≥ 160/100 mmHg -Cerebrovascular event within 3 months of intended randomization -Unstable angina pectoris as judged by the investigator, and/or recent acute myocardial infarction within 3 months of intended randomization -Obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, or active vasculitis because of collagen vascular diseases -Thoracic or cardiac surgery and/or coronary angioplasty within 3 months of intended randomization -Severe uncorrected valvular disease or left ventricular outflow obstruction which, in the opinion of the investigator, requires surgery -Likely to receive cardiac transplant within 6 months after randomization -Uncontrolled ventricular response to atrial fibrillation or flutter, or uncontrolled symptomatic bradyarrhythmias or tachyarrhythmias within 1 month of intended randomization -Physical limitation that, in the judgment of the investigator, would impair cardiopulmonary exercise testing -Receiving oral or intravenous steroids for chronic obstructive pulmonary disease (COPD) -Recipient of any major organ transplant (eg, lung, liver, heart) or receiving renal replacement therapy -Receiving or received chemotherapy and/or radiation therapy for treatment of a malignancy within 12 weeks before randomization, or clinical evidence of current malignancy with the exception of basal cell or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, and prostate cancer if the subject has not received chemotherapy (excluding androgen ablation therapy) within the preceding 12 weeks, had stable localized disease, and had a life expectancy of > 12 months in the opinion of the investigator -Known active, systemic hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, hematologic malignancy, myeloma, hemolytic anemia), or hemolysis because of any cause -Anemia that, in the opinion of the investigator, is because of acute or chronic bleeding -Known to be human immunodeficiency virus (HIV) positive -Serum creatinine > 3.0 mg/dL -Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times the upper limit of the normal range -Recombinant HuEPO or darbepoetin alfa therapy within 12 weeks of intended randomization -Use of an endothelin antagonist, including administration in a clinical study, within 12 weeks of intended randomization -Whole blood or red blood cell (RBC) transfusion within 12 weeks of intended randomization -Contraindication to iron therapy