Recommendations for Anemia

CORLOERecommendationsComment/Rationale
IIbB-RIn patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/mL or 100 to 300 ng/mL if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL (173,174).NEW: New evidence consistent with therapeutic benefit.
See Online Data Supplement D.
Routine baseline assessment of all patients with HF includes an evaluation for anemia in addition to other baseline laboratory measurements. Anemia is independently associated with HF disease severity, and iron deficiency appears to be uniquely associated with reduced exercise capacity. When iron deficiency is diagnosed and after full evaluation for cause, intravenous repletion of iron, especially in the setting of concomitant hepcidin deficiency in HF, may improve exercise capacity and QoL. Studies examining correction of iron deficiency in HF have demonstrated improvement in surrogate endpoints, such as QoL, NT-proBNP, and LVEF; however, controlled trials have been underpowered to detect reductions in hard clinical endpoints. The FAIR-HF (Ferric Carboxymaltose Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (173) demonstrated improvements in NYHA class and functional capacity over a short-term exposure. The CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination with Chronic Heart Failure) trial (174) included a larger cohort of patients (n=304) and demonstrated improvements in 6-minute walk test. A meta-analysis of 5 prospective controlled studies (631 patients) evaluated the effect of intravenous iron on deaths, hospitalizations, and other events in patients with HF and iron deficiency (175). Patients receiving intravenous iron experienced limited but statistically significant improvements in functional capacity and LVEF but no reduction in mortality rate. The FAIR-HF 2 trial is underway to further address the potential benefit of intravenous iron in HF associated with iron deficiency. Therefore, a strong recommendation for intravenous iron repletion must await the results of an appropriately powered trial on morbidity and mortality. There is an uncertain evidence base for oral iron repletion in the setting of anemia associated with HF.
III: No BenefitB-RIn patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity and mortality (176).NEW: Current recommendation reflects new evidence demonstrating absence of therapeutic benefit.
See Online Data Supplement D.
Small studies evaluating the treatment of anemia in patients with HF have suggested a trend toward improvement in functional capacity and reduction in hospitalization with the use of erythropoietin-stimulating agents (177–182), but results have varied (183) and have been limited because of sample size. Although a meta-analysis of 11 RCTs (n=794) comparing erythropoietin-stimulating agents to control in patients with HF demonstrated significant improvements in 6-minute walk, exercise duration, peak Vo2, NYHA functional status, EF, BNP, HF-related hospitalizations, and QoL (184), in the STAMINA-HeFT (Study of Anemia in Heart Failure) trial (183), darbepoetin alfa was not associated with significant clinical benefits. In the largest RCT to date (n=2,278), correction of anemia with darbopoetin alfa did not result in benefit and resulted in a significant increase in the risk of thromboembolic events and a nonsignificant increase in fatal and nonfatal strokes, supporting findings from other trials (176,185–188). In summary, the strongest evidence on erythropoietin-stimulating agent therapy in HF suggests lack of benefit and increased adverse events. Therefore, erythropoietin-stimulating agent therapy cannot be recommended in patients with HF and anemia.