<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (<jats:styled-content style="fixed-case">HF</jats:styled-content>) due to reduced left ventricular ejection fraction (<jats:styled-content style="fixed-case">HFREF</jats:styled-content>). We sought to evaluate the independent effect of anemia on clinical outcomes among those with <jats:styled-content style="fixed-case">HFREF</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Hypothesis</jats:title><jats:p>Anemia is associated with cardiovascular events in patients with heart failure.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The <jats:styled-content style="fixed-case">HF‐ACTION</jats:styled-content> trial was a prospective, randomized trial of exercise therapy vs usual care in 2331 patients with <jats:styled-content style="fixed-case">HFREF</jats:styled-content>. Patients with New York Heart Association class <jats:styled-content style="fixed-case">II</jats:styled-content> to <jats:styled-content style="fixed-case">IV HF</jats:styled-content> and left ventricular ejection fractions of ≤35% were recruited. Hemoglobin (Hb) was measured up to 1 year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb <13 g/<jats:styled-content style="fixed-case">dL</jats:styled-content> and <12 g/<jats:styled-content style="fixed-case">dL</jats:styled-content> in men and women, respectively. Hemoglobin was assessed in 2 models: a global prediction model that had been previously developed, and a modified model including variables associated with anemia and the studied outcomes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female sex, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow‐up of 30 months, the primary outcome of all‐cause mortality or all‐cause hospitalization occurred in 78% of those with anemia and 64% in those without (<jats:italic>P</jats:italic> < 0.001). The secondary outcomes of all‐cause mortality alone,cardiovascular (<jats:styled-content style="fixed-case">CV</jats:styled-content>) mortality or <jats:styled-content style="fixed-case">CV</jats:styled-content> hospitalization, and <jats:styled-content style="fixed-case">CV</jats:styled-content> mortality or <jats:styled-content style="fixed-case">HF</jats:styled-content> hospitalization occurred in 23% vs 15%, 67% vs 54%, and 44 vs 29%, respectively (<jats:italic>P</jats:italic> < 0.001). Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for <jats:styled-content style="fixed-case">HF</jats:styled-content> exacerbations occurred in 67% and 55%, respectively (<jats:italic>P</jats:italic> < 0.001). For the global model, there was an association observed for anemia and all‐cause mortality or hospitalization (adjusted hazard ratio [<jats:styled-content style="fixed-case">HR</jats:styled-content>]: 1.15, 95% confidence interval [<jats:styled-content style="fixed-case">CI</jats:styled-content>]: 1.01‐1.32, <jats:italic>P</jats:italic> = 0.04), but other outcomes were not significant at <jats:italic>P</jats:italic> < 0.05. In the modified model, the adjusted <jats:styled-content style="fixed-case">HR</jats:styled-content> for anemia and the primary outcome of all‐cause mortality or all‐cause hospitalization was 1.25 (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 1.10‐1.42, <jats:italic>P</jats:italic> < 0.001). There were independent associations between anemia and all‐cause death (<jats:styled-content style="fixed-case">HR</jats:styled-content>: 1.11, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 0.87‐1.42, <jats:italic>P</jats:italic> = 0.38), <jats:styled-content style="fixed-case">CV</jats:styled-content> death or <jats:styled-content style="fixed-case">CV</jats:styled-content> hospitalization (<jats:styled-content style="fixed-case">HR</jats:styled-content>: 1.16, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 1.01‐1.33, <jats:italic>P</jats:italic> = 0.035), and <jats:styled-content style="fixed-case">CV</jats:styled-content> death and <jats:styled-content style="fixed-case">HF</jats:styled-content> hospitalization (<jats:styled-content style="fixed-case">HR</jats:styled-content>: 1.27, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 1.06‐1.51, <jats:italic>P</jats:italic> = 0.008).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Anemia modestly is associated with increased rates of death, hospitalization, and <jats:styled-content style="fixed-case">HF</jats:styled-content> exacerbation in patients with chronic <jats:styled-content style="fixed-case">HFREF</jats:styled-content>. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all‐cause mortality and all‐cause hospitalization. Anemia is also associated with combinations of <jats:styled-content style="fixed-case">CV</jats:styled-content> death and <jats:styled-content style="fixed-case">CV</jats:styled-content>/<jats:styled-content style="fixed-case">HF</jats:styled-content> hospitalizations as composite endpoints.</jats:p></jats:sec>