Intravenous iron shows promise for heart failure with reduced ejection fraction

Among iron-deficient patients with heart failure with reduced ejection fraction (HFrEF), receiving intravenous iron supplementation was found to be safe but resulted in mixed findings, according to a study presented at the American College of Cardiology's Annual Scientific Session (ACC.25).

Despite falling short on the primary endpoints related to cardiovascular events, the findings indicated that the time to first cardiovascular death or heart failure hospitalization was about 20% lower in those receiving intravenous iron. The results also showed other indicators of reduced cardiovascular event rates in the first year of iron supplementation when the dosage was highest, along with improvements in secondary endpoints related to quality of life. The trial's findings were also included in a meta-analysis that showed a significant benefit of intravenous iron supplementation in a total of over 7,000 patients with HFrEF across multiple clinical trials.

If we take the totality of evidence from this new trial, which is in line with the previous studies, and take all of the data together in a meta-analysis, it confirms what we have in the current guidelines, namely, that intravenous iron for patients with HFrEF is useful. It has a positive effect on symptoms and quality of life—you feel better, and you function better—and you also get an added bonus in terms of reducing cardiovascular events and heart failure hospitalizations, particularly in the first year after the start of the treatment."

Stefan D. Anker, MD, heart failure cardiologist at Charité-Universitätsmedizin Berlin in Germany and study's first author

HFrEF occurs when the heart becomes too weak to effectively pump blood throughout the body. Iron deficiency, or having a lower-than-normal amount of iron in the blood, is more common in people with heart failure than in the general population, and it is associated with worse heart failure outcomes in addition to symptoms such as fatigue, weakness and shortness of breath. Screening for iron deficiency is recommended for the treatment and management of patients with heart failure.

The trial, called FAIR-HF2, enrolled 1,105 patients with HFrEF at 70 centers in six countries (Germany, Italy, Portugal, Slovenia, Hungary and Poland) All patients had iron deficiency at baseline, defined as a blood ferritin level of less than 100 ng/mL or a blood ferritin level of 100-299 ng/mL with transferrin saturation (TSAT) of less than 20% , another measure of iron levels based on the amount of iron that is bound to the protein transferrin). About two-thirds of the participants were men and their median age was 70 years. Most patients were taking standard heart failure medications and many also had cardiovascular risk factors and comorbidities such as high blood pressure, diabetes or coronary artery disease.

Half of the study participants were randomly assigned to receive intravenous iron supplementation and half received intravenous saline; patients were blinded to their assigned regimen. Patients randomized to iron supplementation received an initial dose of 1,000 mg-2,000 mg of ferric carboxymaltose (an iron preparation given intravenously), with the amount and timing dependent on body weight and baseline hemoglobin. Following the initial dose, participants also received 500 mg of iron intravenously every four months for an average follow-up of 21 months, with those in the placebo group receiving intravenous saline on the same schedule.

According to the results, patients in the treatment group had a 21% lower risk of cardiovascular death or first heart failure hospitalization overall; however, the between-group difference did not meet the threshold for statistical significance for this primary endpoint. The two other primary endpoints—the total rate of heart failure hospitalization (including both first hospitalization and readmissions) and the time to first event of cardiovascular death or heart failure hospitalization among the subgroup of patients with TSAT below 20% at baseline—also did not reach statistical significance despite nominal reductions of 20% and 21%, respectively, among those receiving intravenous iron supplementation.

Since the initial dose of iron supplementation was higher than subsequent doses, the average total iron received among those randomized to the treatment group was 2,040 mg in the first year, 925 mg in the second year and 750 mg in the third year. Researchers said that this variation in the amount of iron received likely influenced the outcomes for the primary endpoints, which showed larger between-group differences at one year compared with two-year and three-year timepoints.

"Intravenous iron was particularly useful in the first year, when the highest dose of iron was given. This suggests that there is a meaningful association between the amount of iron given and the benefit," Anker said. The meta-analysis showed similar patterns in terms of the treatment effects of intravenous iron in the first year of therapy and suggested that further research could help to elucidate the optimal strategy for iron supplementation beyond the first year.

Patients receiving iron supplementation also reported significant quality of life improvements over those receiving saline, as assessed with questionnaires measuring health-related quality of life and perceived well-being.

The results showed no significant difference between groups in terms of safety outcomes including all-cause mortality, cardiovascular mortality or infections at three years.

"Based on the totality of evidence that is now available, we can with certainty say that intravenous iron therapy at the doses given in FAIR-HF2 and other recent trials is safe," Anker said.

The trial's follow-up procedures and duration were negatively impacted by the COVID-19 pandemic, budgetary constraints and a change in international heart failure treatment guidelines which led some patients to stop their assigned regimen early. As a result, researchers said that the observed differences between groups were of a lower magnitude than the study was designed to assess, but nevertheless consistent with the overall direction of findings in previous trials and meta-analyses.

Since the FAIR-HF2 trial only included patients with HFrEF, Anker said that additional research is needed to determine whether intravenous iron supplementation also brings benefits for people with heart failure with preserved ejection fraction, a different type of heart failure. In addition, based on the results of the meta-analysis, he said that it will be important to better understand differences in the cardiovascular benefits of intravenous iron supplementation in women versus men.

The study was funded by DZHK Germany and CSL Vifor.

The results of the FAIR-HF2 trial were simultaneously published in the Journal of the American Medical Association and the meta-analysis was simultaneously published online in Nature Medicine at the time of presentation.