Phase 3 trial with ferric carboxymaltose in HFrEF does not meet hierarchical primary endpoint

ESC Congress 2023 In HFrEF patients with iron deficiency, IV ferric carboxymaltose resulted in a modest albeit not statistically significant improvement in the hierarchical composite outcome of all-cause mortality, HF hospitalization, and change in exercise capacity.

Presented at the ESC congress 2023 by: Robert Mentz, MD - Durham, NC, USA

Introduction and methods

Iron deficiency is very common in HF, affecting ≥50% of patients. It is strongly associated with worse quality of life, less exercise capacity, more HF hospitalizations, and increased mortality. Intravenous iron therapy may improve some clinical outcomes, but more evidence is needed on its effect on hospitalization and survival.

The HEART-FID (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT conducted in 3065 ambulatory patients with chronic HFrEF (LVEF ≤40%), NYHA class II–IV symptoms, and iron deficiency. Participants were randomly assigned to intravenous ferric carboxymaltose (FCM) or placebo, given every 6 months as applicable, in addition to standard HF therapy. Median follow-up duration was 1.9 years (IQR: 1.3–3.0).

The primary endpoint was a hierarchical composite outcome of all-cause mortality at 12 months, HF hospitalizations at 12 months, and change in 6-minute walk distance (6MWD) from baseline to 6 months. The top secondary endpoint was time to first HF hospitalization or CV death during follow-up. The prespecified significance level was set at 0.01.

Main results

• All-cause mortality at 12 months was observed in 131 patients (8.6%) treated with FCM and 158 placebo-treated patients (10.3%) (absolute risk reduction: 1.7%; 20% more wins).
• The total number of HF hospitalizations at 12 months was 297 in the FCM group and 332 in the placebo group, corresponding to 270 fewer HF hospitalization days in the FCM group.
• The mean change in 6MWD from baseline to 6 months was 8 m (SD: 60) in the FCM group versus 4 m (SD: 59) in the placebo group (benefit: 4 m; 11% more wins).
• Taken together, there was no statistically significant difference in the incidence of the hierarchical primary endpoint (P=0.019; unmatched win ratio: 1.10; 99%CI: 0.99–1.23).
• The rate of the top secondary endpoint was 475/1532 (31.0%) in the FCM group and 494/1533 (32.2%) in the placebo group (16.0 vs. 17.3 events per 100 patient-years; HR: 0.93; 96%CI: 0.81–1.06).

Conclusion

In chronic HFrEF patients with iron deficiency, intravenous FCM treatment resulted in a modest albeit not statistically significant improvement in the hierarchical composite outcome of all-cause mortality, HF hospitalization, and change in 6MWD. Still, Dr. Mentz believes the total body of evidence supports the clinical benefits and safety of intravenous FCM in patients with HFrEF and iron deficiency.

• Our reporting is based on the information provided at the ESC Congress -

The results of this study were simultaneously published in N Engl J Med. Watch a video by Robert Mentz