Assessment and treatment of iron deficiency in heart failure patients

Although several studies have documented the good effect of treatment with intravenous iron for iron deficiency in acute and chronic heart failure with reduced ejection fraction (EF) (corresponding to »systolic« heart failure), the implementation of this knowledge is slow [1]. We have therefore developed a simple treatment algorithm based on published data to simplify handling in clinical practice (Figure 1).

Prevalence, causes and mechanisms

Iron, bound to heme in hemoglobin and myoglobin, is essential for oxygen transport in the erythrocytes as well as storage of oxygen and energy production in tissues, not least in muscles [2].

Iron deficiency is an important cause of anemia and leads to impaired function in both the myocardium and skeletal muscle [3].

In heart failure, iron deficiency, regardless of the concomitant presence of anemia, is related to reduced quality of life, impaired physical performance and increased cardiovascular and total mortality [4]. In chronic heart failure, up to half of the patients may have iron deficiency, with or without concomitant anemia [5,6]. The incidence of iron deficiency increases with increasing NYHA class, and it is caused both by absolute iron deficiency with depleted depots and by inflammation-related iron deficiency with low availability of the iron found in the depots (functional iron deficiency). Absolute iron deficiency can be caused by increased losses through bleeding, low intake, reduced absorption from the small intestine, or effects of platelet inhibition and anticoagulants. In systemic inflammation, which is common in patients with heart failure, hepcidin production increases in the liver, blocking iron uptake from the gut and release from stores.

Renal failure is another important cause of anemia in heart failure patients, caused by a combination of iron deficiency, inflammation and erythropoietin deficiency. However, it does not give rise to the same considerations regarding further investigation of underlying causes and is therefore not discussed further here.


Serum ferritin <30 µg/l together with transferrinmättnad <16 percent indicates alltid absolute iron deficiency. In simultaneous inflammation, ferritin levels in plasma reflect non-mobilizable iron deposits, and ferritin is also an acute phase reactant, which makes the assessment difficult. In clinical studies of heart failure patients, iron deficiency is considered to be present at ferritin <100 µg/l, or at ferritin <300 µg/l, while transferrin saturation is <20 percent. In difficult-to-interpret situations, the analysis of soluble transferrin receptor in serum can help, since elevated levels always reflect absolute iron deficiency, regardless of concomitant inflammation. European guidelines for heart failure recommend evaluation of iron status in all patients with heart failure and treatment with iron carboxymaltose for iron deficiency in patients with EF <50 percent. [4]. But there is still uncertainty in the assessment of underlying causes beyond the heart failure and a lack of recommendations regarding the practical clinical management. Gastrointestinal cancer appears to be common in heart failure with iron deficiency [7]with no definite difference between patients with or without anemia, defined as Hb <120 g/l.

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Oral iron treatment has been shown to have no effect on studied variables in chronic heart failure. The cause is a combination of gastrointestinal intolerance, reduced absorption due to edema of the small intestine, and systemic inflammation with hepcidin blocking intestinal iron absorption. However, several studies have shown positive effects of intravenous iron on symptoms, quality of life and functional parameters in patients with chronic heart failure and reduced ejection fraction [8]. FAIR-HF enrolled 459 patients with NYHA class II–III heart failure with EF <40–45 percent and iron deficiency, with or without concomitant anemia [9]. Patients were randomized to placebo or 200 mg of iron carboxymaltose intravenously once a week until iron stores were normalized and then 200 mg intravenously every four weeks. At the 24-week follow-up, intravenous iron was found to improve quality of life according to the validated Kansas City cardiomyopathy questionnaire, the NYHA classification, and the 6-minute walk test. The results were neither dependent on EF nor Hb levels at the start of treatment.

In the CONFIRM-HF trial, 304 patients in NYHA II–III, EF <45 percent, and iron deficiency were randomized to treatment with 500–1,000 mg of ferric carboxymaltose or placebo during the first week of treatment [8]. If iron status did not normalize, patients in the active arm received additional intravenous iron. The total iron doses amounted to 500–3,500 mg. Treatment with intravenous iron significantly improved the 6-minute walk test after 24 weeks. The statistical difference against the placebo group remained after 52 weeks. In addition, the iron treatment improved fatigue, self-perceived health and NYHA class, and reduced the number of hospitalizations due to heart failure. In AFFIRM-AHF, 1,132 patients hospitalized with acute heart failure, EF <50 percent and iron deficiency at discharge were randomized to ferric carboxymaltose or placebo [10]. The treatment resulted in better function and quality of life and a lower risk of readmission to hospital due to worsening heart failure, still without differences between patients with initial Hb above or below 120 g/l.

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Treatment with iron carboxymaltose should therefore be considered to improve symptoms, level of function and quality of life and reduce the risk of hospitalization for heart failure in heart failure patients with iron deficiency and EF <45 percent, respectively patients with EF 50 percent) and health economics.

Treatment risks

Overall, the rate of infusion reactions with modern intravenous iron preparations is very low, even lower than with other intravenous drug therapies. The frequency of hypersensitivity reactions is <1 percent, which was recently confirmed in a large meta-analysis [11]. Anaphylactic reactions are very rare. The majority of infusion reactions are due to interaction between free iron and vascular endothelium, release of nitric oxide and non-allergic complement activation and cease when the infusion is stopped [12]. The infusion can then be restarted after approximately 15 minutes at a slower infusion rate. If an anaphylactic reaction is suspected, the treatment should of course not be resumed.

Hypophosphatemia, which is usually asymptomatic, is a side effect of intravenous iron therapy that has received attention in recent years. The risk is significantly greater for ferric carboxymaltose than for ferric derisomaltose. The mechanism is mapped in detail [13], and the hypophosphatemia is due to an increase in intact fibroblast growth factor 23, probably mediated by the carbohydrate component of ferric carboxymaltose. The increase is accompanied by changes in 1,25-dihydroxyvitamin D, calcium and parathyroid hormone, which may be long-lasting, even after normalization of fibroblast growth factor 23. Osteomalacia may rarely develop as a result of prolonged hypophosphatemia after repeated infusions, but otherwise the clinical consequences are not yet clarified.

Algorithm for further investigation of patients

Based on available data and ESC recommendations, we suggest that blood status, ferritin and transferrin saturation be analyzed regularly in all patients with heart failure and EF <50 percent [4]. Treatment with intravenous iron should be started as soon as iron deficiency is detected and continued until the iron deficiency is eliminated. In addition, underlying causes of the iron deficiency should be evaluated in accordance with Figure 1. The decision to investigate the iron deficiency further must be made by the responsible doctor in consultation with the patient and relatives and based on the probability that factors other than the heart failure itself are behind the iron deficiency, the patient's risk factors and other symptoms and the patient's situation, general condition and treatment options. Investigation of possible chronic blood loss should, based on clinical suspicion, primarily focus on the gastrointestinal tract [7], but also urinary tract and gynecological causes. Furthermore, transglutaminase antibodies should be analyzed in view of possible underlying celiac disease.

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Also note that iron therapy can raise iron stores and hemoglobin and mask blood loss and thus these underlying causes, even if Hb was initially >120 g/l.

The treatment effect must be followed up, and after the treatment goal has been achieved, the patient’s blood and iron status should be monitored approximately every two months, and new treatment with intravenous iron should be given if iron deficiency develops again.

If further investigation is not considered possible or meaningful, the patient should still receive treatment for their iron deficiency, in light of proven positive effects on quality of life and physical performance, reduced need for hospitalization and possibly even lower mortality [10].

Treatment of iron deficiency in heart failure patients with iron carboxymaltose is also likely to be cost-effective [14].


Iron deficiency is a common comorbidity in patients with heart failure. Treatment with intravenous iron has been shown to improve the patients’ symptoms, functional status and quality of life and reduce the need for hospitalization for heart failure. The studies published so far are based on ferric carboxymaltose, but corresponding studies with ferric derisomaltose are ongoing. In the case of established iron deficiency and in connection with iron treatment, it is important that other causes of iron deficiency than the heart failure itself are taken into account, especially chronic blood loss via the intestine, including malignancies. The algorithm we present provides support for handling treatment and decision-making for further investigation of heart failure patients with iron deficiency and can probably be implemented without the need for additional resources.

Potential affiliations or relationships: All authors have received fees for lectures and webinars on behalf of Vifor Pharma and Pharmacosmos. The companies have not paid compensation for or influenced the design of the article.

The medical journal. 2022;119:22014

The medical journal 38-39/2022 2022-09-21

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