Name of the Study: HEART-FID/ Baseline characteristics of patients in the randomized study to investigate the efficacy and safety of ferric carboxymaltose as treatment for heart failure with iron deficiency

Reviwer: Dr. Cemalettin Akman

Published Congress: ESC 2023

Link: https://www.nejm.org/doi/pdf/10.1056/NEJMe2308305

Background:

In patients with heart failure, iron deficiency is common and is associated with worse symptoms and outcomes than those in patients with heart failure without iron deficiency. The IRONOUT HF trial showed that oral iron therapy did not improve exercise capacity in patients who had heart failure with a reduced ejection fraction and iron deficiency. In contrast, other trials (AFFIRM-AHF, IRONMAN trials) showed that intravenous ferric carboxymaltose treatment improved the quality of life and functional capacity in patients who had heart failure with a reduced ejection fraction and iron deficiency. Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed.

Objective:

The aim of this study was to evaluate the incidence of heart failure death and hospitalization with ferric carboxymaltose therapy in heart failure patients with reduced ejection fraction and iron deficiency.

Methods:

Among the 8195 patients screened in the HEART-FID study, 3065 patients (Lvef < % 40 with iron deficiency) were included in this double-blind, randomized trial. Intravenous ferric carboxymaltose or placebo therapy was administered in two doses 7 days apart. Follow-up occurred every 3 months, with ferric carboxymaltose or placebo administered every 6 months on the basis of hemoglobin and iron indexes. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance.

Results:

At 12 months, death had occurred in 131 patients (8.6%) in the ferric carboxymaltose group and in 158 (10.3%) in the placebo group; there were 297 and 332 total hospitalizations for heart failure, respectively, by 12 months; and the mean (±SD) change in the 6-minute walk distance from baseline to 6 months was 8±60 and 4±59 m, respectively (overall P = 0.02). During the follow-up period, cardiovascular death or hospitalization for heart failure (main secondary outcome) occurred in 475 patients (31.0%) in the ferric carboxymaltose group and in 494 patients (32.2%) in the placebo group (hazard ratio, 0.93; 96% CI, 0.81 to 1.06). The mean (±SD) change in the 6-minute walk distance from baseline to 12 months was 5±71 m in the ferric carboxymaltose group and 4±72 m in the placebo group. Death from any cause during the follow-up period, a prespecified exploratory outcome, occurred in 361 patients (23.6%) in the ferric carboxymaltose group and in 376 patients (24.5%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.78 to 1.05); the hazard ratio for death from any cause through month 12 was 0.82 (95% CI, 0.65 to 1.05). The number of patients with a serious adverse event occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group). Seven adverse events that occurred in the ferric carboxymaltose group during the treatment period were classified as angioedema (two events) or hypersensitivity (five events) and these side effects have been treated. Although improvement was observed in the group receiving ferric carboxymaltose treatment at 6-minute walking distance, no statistically significant difference was found.

Conclusion:

In the AFFIRM-AHF study, the rate of hospitalization for heart failure was found to be lower in the ferric carboxymaltose group, but in the HEART-FID study, no statistically significant difference was found between the two groups. In the IRONMAN study, cardiovascular death was similar to placebo, although hospitalizations decreased. The lack of a long-term reduction in hospitalizations for heart failure in this study was unexpected. Several factors may be responsible for this finding. The patient population in this meta-analysis was a lower-risk population than the population with acute heart failure in the AFFIRM-AHF trial (all patients enrolled while hospitalized) and the IRONMAN trial (15% of patients enrolled while hospitalized).

Interpretations:

Among patients with chronic systolic heart failure and iron deficiency, IV ferric carboxymaltose although there is no statistically significant difference was associated with a marginal improvement in cardiovascular outcomes compared with placebo. IV ferric carboxymaltose appeared to be safe. Further research on the topic appears warranted.