Potential Pathophysiologic Role of Hemoglobin in HF: An Unresolved Issue

Anemia and reduced hemoglobin have been associated with HF for decades. Until recently the assumption was that the observed reduction in hemoglobin was consistent with "anemia of chronic disease," was not of prognostic significance and did not need to be treated. A number of recent studies demonstrated a significant association between reduced hemoglobin and a number of adverse outcomes, including exercise capacity, quality of life, and risk of death or hospitalization.

Prevalence and Pathogenesis. The prevalence of reduced hemoglobin and anemia in HF varies widely. Depending on the anemia criterion used and patient population studied, from 10% to 70% of HF patients meet criteria for anemia.113 Reduced renal function is increasingly common in patients with HF and is a well-documented cause of anemia.114 Anemia is common in elderly patients with HF, especially those with a history of hospitalization for HF, and patients with advanced clinical class are more likely to have reduced hemoglobin. A prospective ongoing study of patients with HF seen in specialty clinics and community cardiology practices suggests approximately 30 percent of patients with HF are anemic.115,116

The pathogenesis of anemia in patients with HF is uncertain. Several potential mechanisms have been proposed, including impaired renal function, malabsorption, nutritional deficiency and cytokine activation.114,117-120

Morbidity and Mortality. Preliminary analysis of the results of prospective quality of life measurements in unselected outpatients with HF seen in specialty clinics or community cardiology practices suggests that reduced hemoglobin is associated with poorer quality of life.121 Reduced hemoglobin has been shown to be a risk factor for hospitalization for HF. A retrospective study of Medicare patients reviewed the association between outcome and hemoglobin in 665 patients admitted to community hospitals for HF.122 The risk of hospitalization was significantly increased in patients who also had anemia and was nearly doubled among those patients with anemia and chronic kidney disease (defined as a serum creatinine >1.4 mg/dL for women and >1.5 mg/dL for men).

A number of retrospective database studies have demonstrated that reduced hemoglobin is significantly associated with increased mortality in patients with HF.123-125 Early work in a high-risk subset of patients with HF suggests that dilutional anemia, even more than true anemia, is associated with a poor prognosis. Hemodilution can worsen HF by impairing peripheral oxygen delivery, and the volume overload that occurs with hemodilution increases pulmonary capillary wedge pressure. As a result, survival in patients with HF and dilutional anemia is decreased compared with that of patients with HF and true anemia.126

Therapeutic Experience. There are very preliminary data to suggest that increasing hemoglobin may have beneficial effects in patients with HF. A recent single-center, small-scale randomized, single-blind, placebo-controlled study evaluated the effect of 3 months of erythropoietin treatment on exercise capacity in 26 patients with anemia and New York Heart Association (NYHA) class III-IV HF.127 Significant improvement in peak oxygen consumption (VO<span class="sub">2 max) occurred with erythropoietin treatment versus no significant change in the control patients. In the and Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial, 200 mg of intravenous iron improved symptoms, functional capacity, and quality of life in patients with chronic heart failure, reduced LVEF, and iron deficiency.128

Possible Adverse Effects. Although the association studies and the preliminary clinical investigations suggest potential benefit from augmenting hemoglobin in patients with HF, there are theoretical concerns about this form of therapy. Erythropoietin therapy has been associated with worsening hypertension in 20% to 30% of patients on hemodialysis.129 Raising the hemoglobin level could adversely affect viscosity, which could lead to increased risk of thrombosis. Increased risk of thrombosis also could occur as a result of increased platelet activation, increased blood viscosity, or effects on the levels of proteins C and S.130-135

Summary. Retrospective analysis of database and early interventional studies raises the possibility that augmenting hemoglobin concentration may benefit patients with HF. However, given the risk carried by higher hemoglobin levels, more definitive data on the clinical benefits of anemia therapy in HF are needed. Several important questions remain unanswered concerning the ideal implementation of this therapy, including the optimal hemoglobin level and the appropriate rate of rise of hemoglobin when therapy is initiated. Randomized placebo controlled trials in patients with HF, including Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF), and IRON-HF are underway to establish the safety and efficacy of this and other treatment strategies.