Intravenous (IV) iron supplementation with ferric carboxymaltose was found to be well tolerated and improve quality of life in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency, but it did not significantly reduce the time to first HF hospitalization or cardiovascular death, including among patients with a transferrin saturation <20%, or reduce the total number of HF hospitalizations, according to the FAIR-HF2 study presented at ACC.25 in Chicago and simultaneously published in JAMA.

The investigator-initiated study conducted at 70 clinics in six countries in Europe from March 2017 to November 2023, randomized 1,105 patients (mean age 70 years, 33% women) with HFrEF (LVEF ≤45%) and iron deficiency (serum ferritin level <100 ng/mL or 100 ng/mL to 299 ng/mL if the transferrin saturation was <20%) to treatment with an initial IV dose of ferric carboxymaltose of 1,000-2,000 mg followed by 500 mg every four months (n=558) or IV saline placebo (n=547). Patients were blinded to their treatment.

Most patients were taking standard HF medications and many had cardiovascular risk factors and comorbidities, such as high blood pressure, diabetes or coronary artery disease.

Results showed that after a median follow-up of 16.6 months, in the treatment group vs. placebo group, there was a nonsignificant reduction in each of the three primary outcomes: a 21% lower risk of time to cardiovascular death or first HF hospitalization, a 20% reduction in total HF hospitalizations, and a 21% reduction in time to cardiovascular death or first HF hospitalization in patients with low transferrin saturation. There were larger between-group differences between the first and second year of treatment, which could be caused by the larger initial dose of iron supplementation.

For secondary outcomes, patients in the ferric carboxymaltose group reported a significant increase in quality of life. In terms of safety, there was a comparable rate of serious adverse events in the treatment and placebo groups (48.2% vs. 49.9%; p=0.61).

The investigators noted a high rate of treatment discontinuation (34% in the ferric carboxymaltose group vs. 38% in the placebo group), which they attribute to the COVID-19 pandemic. For the same reason, the length of follow-up was shorter than initially planned.

"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," said the study's first author, Stefan D. Anker, MD, PhD. "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 [HF] hospitalizations, particularly in the first year after the start of the treatment."