By Van Selby, MD

Assistant Professor of Medicine, UCSF Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SOURCE: Ponikowski P, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Euro Heart J 2015;36:657-668.

Iron deficiency (ID) is common in patients with heart failure (HF), and its presence is associated with reductions in functional capacity, quality of life, and survival. Several clinical trials have shown improved outcomes in patients with HF and ID who are treated with IV iron. However, these trials only administered IV iron for short periods of time, and the long-term effects of IV iron in these patients are not well understood.

To address the effects of long-term IV iron, the authors conducted the Ferric Carboxymaltose evaluation on performance in patients with iron deficiency in combination with chronic heart failure (CONFIRM-HF). Eligible participants had stable HF with NYHA functional class II or III symptoms, ejection fraction ≤ 45%, and presence of ID as defined as serum ferritin level < 100 ng/mL, or between 100 and 300 ng/mL if the transferrin saturation was less than 20%. Subjects were randomized to either IV iron or placebo. Those in the iron arm received ferric carboxymaltose (FCM) at doses of 500-2000 mg. After two initial doses at study initiation and week 6, maintenance doses were given every 12 weeks if ID was still present. The primary endpoint was change in the 6-minute walk test distance.

Three hundred and four subjects were randomized. At 24 weeks, the difference in the 6-minute walk distance between the IV iron and placebo groups was 33 ± 11 meters (P = 0.002). Subjects randomized to IV iron also saw significant improvement in NYHA class (P = 0.004), global assessment, and quality of life, and these benefits persisted at 52 weeks of follow-up. The risk of hospitalization due to worsening HF was also significantly lower in the IV iron group (HR, 0.39; P = 0.009). The benefits were observed regardless of whether or not anemia was present. There were no differences in adverse events between the groups. The authors conclude that treatment of stable, symptomatic, iron-deficient HF patients with FCM over a 1-year period results in sustained improvement in functional capacity, symptoms, and quality of life, and may reduce hospitalizations due to worsening HF.

COMMENTARY

CONFIRM-HF adds to the growing literature demonstrating benefit from IV iron therapy in patients with HF and ID. The FAIR-HF trial previously showed that treatment with IV iron is associated with improvements in functional status, exercise tolerance, and QOL over a 6-month follow-up. The present study strengthens these findings by showing the benefits persist after 1 year of treatment. Intravenous iron was well-tolerated and the benefits were seen in all subgroups.

Although the primary outcome was 6-minute walk distance, the reduction in HF-related hospitalization is particularly promising and consistent with previous trials of IV iron for ID in HF. In an accompanying editorial, Brunner-La Rocca and colleagues pool the results of CONFIRM-HF with three previous studies. The summary risk ratio for heart failure hospitalization in patients receiving IV iron compared to placebo was an impressive 0.33 (95% CI, 0.19-0.56). It is also interesting that the beneficial effects of IV iron were observed regardless of whether anemia is present. This is similar to what has been observed in previous studies, and highlights our incomplete understanding of the mechanism by which these patients benefit from IV iron.

One particularly useful aspect of CONFIRM-HF is the dosing scheme and administration protocol used. Subjects received bolus doses of IV iron (administered over 1 minute) at baseline and week 6, with additional doses only given as needed. Seventy-five percent of subjects required only two injections to correct and maintain iron levels. This schedule is entirely compatible with real-world implementation, and easier than the schedules used in several previous studies. Oral iron has not been well studied in this population.

So is it time to start giving IV iron to all patients with HF and ID? Current ACC/AHA guidelines mention the FAIR-HF trial, but do not make any specific recommendations regarding the management of anemia or ID in HF patients. European guidelines suggest testing for iron deficiency in HF, but similarly do not make strong recommendations regarding IV iron. We will need to see a larger randomized trial with a “harder” primary endpoint than 6-minute walk distance before we see a class I indication for IV iron.

At this point, for HF patients who remain symptomatic despite adherence to standard guideline recommended therapies and correction of other comorbidities, treating ID with IV iron is a reasonable intervention to improve symptoms and possibly reduce HF-related hospitalizations. It is important to monitor iron levels after initial treatment, as patients may require occasional maintenance doses. Given its ease of use, the treatment protocol from CONFIRM-HF seems like a reasonable dosing strategy for this purpose.