Pharmacology Consult

Ironing it out: Management of iron deficiency in HF

Iron deficiency is prevalent in up to 30% to 50% of patients with stable, chronic HF. More than 30% of these patients do not have anemia or abnormalities in hematologic indices. The prevalence is higher in women and in those with advanced HF, heightened inflammation and anemia.

Priyam Mithawala

Iron deficiency is defined differently in chronic inflammatory conditions such as chronic HF, with a higher cutoff for ferritin. In chronic HF, iron deficiency is defined as ferritin less than 100 g/L for absolute iron deficiency (depleted iron stores) or ferritin 100 g/L to 300 g/L and transferrin saturation less than 20% for functional iron deficiency (iron unavailable for dedicated tissues).

Defining iron deficiency in acute HF is more challenging due to plasma volume variations. Currently, it is unknown whether volume-independent or plasma volume-corrected indices would identify true iron deficiency in acute HF.

Janna C. Beavers

Etiology, pathophysiology

Iron is pivotal for the normal functioning of citric acid cycle enzymes and reactive oxygen species scavenging enzymes. Myocardial iron deficiency in HF is associated with reduced activity of citric acid cycle enzymes and reduced expression of reactive oxygen species scavenging enzymes.

Lower activity of the citric acid cycle can impair the normal bioenergetics of cardiomyocytes, which can lead to reduced maximal exercise capacity due to limited left ventricular contractile reserve. Decreased reactive oxygen species scavenging enzymes in myocardial iron deficiency causes an increase in local oxidative stress. This leads to further myocardial damage. The pathophysiology of iron deficiency in HF with reduced ejection fraction is shown in the Figure.

Source: Adapted from Rocha BML, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2017.12.027.

Iron homeostasis is impaired in HF. Progressive HF not only causes iron deficiency, but iron deficiency also induces HF. Regardless of anemia, iron deficiency has been shown to be independently associated with increased hospitalizations and mortality. Furthermore, patients with isolated iron deficiency have a worse prognosis compared with those with anemia and no iron deficiency.

Management of iron deficiency

Iron replacement in HF has been studied primarily in the ambulatory setting with IV therapy with ferric carboxymaltose or iron sucrose (Table 1). The largest studies evaluating clinical outcomes with IV iron are FAIR-HF, CONFIRM-HF and EFFECT-HF. FAIR-HF and CONFIRM-HF both demonstrated an improvement in patient global assessment, NYHA classification, 6-minute walk test distance and quality of life via the Kansas City Cardiomyopathy Questionnaire (KCCQ) with iron replacement. The FAIR-HF study did not show a significant improvement in hospitalizations or survival, although a trend toward reduced hospitalizations emerged. In contrast, CONFIRM-HF showed a significant reduction in hospitalizations; however, there was no difference in mortality. EFFECT-HF concluded that IV iron therapy improved exercise capacity.

Another trial, IRONOUT, studied the effects of oral iron compared with placebo. In this study, oral iron did not change peak oxygen consumption or 6-minute walk test distance. Administration of oral iron only demonstrated a small improvement in iron stores, in contrast to IV iron studies. The difference in outcomes may be related to hepcidin levels. Patients with higher hepcidin levels did not respond as well to oral iron replacement, whereas those with lower hepcidin levels experienced an improvement in quality of life. Other theories for the differing results between oral and IV therapy include the effect of bioavailability on absorption, compliance, potential gastrointestinal adverse effects, and the amount of time required to fully replete iron stores.

Source: Tables and figure provided by authors.

Other therapies for anemia have demonstrated negative outcomes in this patient population. Blood transfusions do not improve clinical outcomes and carry risk for adverse effects, including infection, allergic reactions and hemolytic reactions. Erythropoiesis-stimulating agents, such as darbepoetin (Aranesp, Amgen) or epoetin (Epogen/Procrit, Amgen), are commonly used in patients with chronic kidney disease and anemia. RED-HF studied darbepoetin in HF patients and showed no clinical improvement over placebo with increased thromboembolic complications.

Practical considerations

Selection of an IV iron product is based on available evidence, which supports the use of ferric carboxymaltose or iron sucrose. The clinical decision may be based on cost, availability of products at institutions or complexity of dosing regimens.

The total dose of iron should be based on the individual patient’s iron deficit. This is traditionally calculated using the Ganzoni formula: [weight (kg) x (target hemoglobin – actual hemoglobin) x 2.4 + iron stores]. The dose and regimen selected may be affected by the patient’s setting.

As mentioned earlier, evidence for IV iron in the HF population is limited to the ambulatory setting for stable patients. However, the safety of an accelerated regimen of IV ferric gluconate twice daily for hospitalized patients has been studied, demonstrating safety in the acute setting.

Clinical decisions may be made based on patient-specific factors, product availability and ease of administration. The most commonly reported adverse reaction with IV iron administration is hypotension, which is often resolved with a reduction in the infusion rate.

2017 guideline update

The 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guideline states that IV iron may be reasonable in NYHA class II/III HF patients (level of evidence II-B). The 2016 European Society of Cardiology guidelines recommend IV iron in patients with symptomatic HFrEF to improve functional status and alleviate symptoms (level of evidence II-A). Based on the correction algorithm proposed in a recent state of art review published in the Journal of the American College of Cardiology, IV iron should be administered to patients with NYHA class II/III HF with ejection fraction less than 40% to 45% and hemoglobin less than 13.5 g/dL after excluding secondary causes of iron deficiency anemia and correcting other causes such as folate, B12 and hypothyroidism.

Ongoing studies will focus on morbidity and mortality, HF with preserved ejection fraction and acute HF (Table 2).

Disclosures: The authors report no relevant financial disclosures.

Iron deficiency is prevalent in up to 30% to 50% of patients with stable, chronic HF. More than 30% of these patients do not have anemia or abnormalities in hematologic indices. The prevalence is higher in women and in those with advanced HF, heightened inflammation and anemia.

Priyam Mithawala

Iron deficiency is defined differently in chronic inflammatory conditions such as chronic HF, with a higher cutoff for ferritin. In chronic HF, iron deficiency is defined as ferritin less than 100 g/L for absolute iron deficiency (depleted iron stores) or ferritin 100 g/L to 300 g/L and transferrin saturation less than 20% for functional iron deficiency (iron unavailable for dedicated tissues).

Defining iron deficiency in acute HF is more challenging due to plasma volume variations. Currently, it is unknown whether volume-independent or plasma volume-corrected indices would identify true iron deficiency in acute HF.

Janna C. Beavers

Etiology, pathophysiology

Iron is pivotal for the normal functioning of citric acid cycle enzymes and reactive oxygen species scavenging enzymes. Myocardial iron deficiency in HF is associated with reduced activity of citric acid cycle enzymes and reduced expression of reactive oxygen species scavenging enzymes.

Lower activity of the citric acid cycle can impair the normal bioenergetics of cardiomyocytes, which can lead to reduced maximal exercise capacity due to limited left ventricular contractile reserve. Decreased reactive oxygen species scavenging enzymes in myocardial iron deficiency causes an increase in local oxidative stress. This leads to further myocardial damage. The pathophysiology of iron deficiency in HF with reduced ejection fraction is shown in the Figure.

Source: Adapted from Rocha BML, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2017.12.027.

Iron homeostasis is impaired in HF. Progressive HF not only causes iron deficiency, but iron deficiency also induces HF. Regardless of anemia, iron deficiency has been shown to be independently associated with increased hospitalizations and mortality. Furthermore, patients with isolated iron deficiency have a worse prognosis compared with those with anemia and no iron deficiency.

Management of iron deficiency

Iron replacement in HF has been studied primarily in the ambulatory setting with IV therapy with ferric carboxymaltose or iron sucrose (Table 1). The largest studies evaluating clinical outcomes with IV iron are FAIR-HF, CONFIRM-HF and EFFECT-HF. FAIR-HF and CONFIRM-HF both demonstrated an improvement in patient global assessment, NYHA classification, 6-minute walk test distance and quality of life via the Kansas City Cardiomyopathy Questionnaire (KCCQ) with iron replacement. The FAIR-HF study did not show a significant improvement in hospitalizations or survival, although a trend toward reduced hospitalizations emerged. In contrast, CONFIRM-HF showed a significant reduction in hospitalizations; however, there was no difference in mortality. EFFECT-HF concluded that IV iron therapy improved exercise capacity.

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Another trial, IRONOUT, studied the effects of oral iron compared with placebo. In this study, oral iron did not change peak oxygen consumption or 6-minute walk test distance. Administration of oral iron only demonstrated a small improvement in iron stores, in contrast to IV iron studies. The difference in outcomes may be related to hepcidin levels. Patients with higher hepcidin levels did not respond as well to oral iron replacement, whereas those with lower hepcidin levels experienced an improvement in quality of life. Other theories for the differing results between oral and IV therapy include the effect of bioavailability on absorption, compliance, potential gastrointestinal adverse effects, and the amount of time required to fully replete iron stores.

Source: Tables and figure provided by authors.

Other therapies for anemia have demonstrated negative outcomes in this patient population. Blood transfusions do not improve clinical outcomes and carry risk for adverse effects, including infection, allergic reactions and hemolytic reactions. Erythropoiesis-stimulating agents, such as darbepoetin (Aranesp, Amgen) or epoetin (Epogen/Procrit, Amgen), are commonly used in patients with chronic kidney disease and anemia. RED-HF studied darbepoetin in HF patients and showed no clinical improvement over placebo with increased thromboembolic complications.

Practical considerations

Selection of an IV iron product is based on available evidence, which supports the use of ferric carboxymaltose or iron sucrose. The clinical decision may be based on cost, availability of products at institutions or complexity of dosing regimens.

The total dose of iron should be based on the individual patient’s iron deficit. This is traditionally calculated using the Ganzoni formula: [weight (kg) x (target hemoglobin – actual hemoglobin) x 2.4 + iron stores]. The dose and regimen selected may be affected by the patient’s setting.

As mentioned earlier, evidence for IV iron in the HF population is limited to the ambulatory setting for stable patients. However, the safety of an accelerated regimen of IV ferric gluconate twice daily for hospitalized patients has been studied, demonstrating safety in the acute setting.

Clinical decisions may be made based on patient-specific factors, product availability and ease of administration. The most commonly reported adverse reaction with IV iron administration is hypotension, which is often resolved with a reduction in the infusion rate.

PAGE BREAK

2017 guideline update

The 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guideline states that IV iron may be reasonable in NYHA class II/III HF patients (level of evidence II-B). The 2016 European Society of Cardiology guidelines recommend IV iron in patients with symptomatic HFrEF to improve functional status and alleviate symptoms (level of evidence II-A). Based on the correction algorithm proposed in a recent state of art review published in the Journal of the American College of Cardiology, IV iron should be administered to patients with NYHA class II/III HF with ejection fraction less than 40% to 45% and hemoglobin less than 13.5 g/dL after excluding secondary causes of iron deficiency anemia and correcting other causes such as folate, B12 and hypothyroidism.

Ongoing studies will focus on morbidity and mortality, HF with preserved ejection fraction and acute HF (Table 2).

Disclosures: The authors report no relevant financial disclosures.