Effects of ferric carboxymaltose for iron deficiency in acute HF by hemoglobin level
Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis
Introduction and methods
In HF patients, both iron deficiency and anemia are associated with an increased risk of hospitalization and mortality [1-7]. Interestingly, in patients with chronic HF, baseline hemoglobin levels do not influence the prognostic role of iron deficiency and the beneficial effects of treatment with ferric carboxymaltose (FCM) [1,4,8,9]. The role of iron deficiency and its treatment in relation to hemoglobin levels remains to be elucidated in patients with recent acute HF (AHF), a population with higher morbidity and mortality than a chronic HF population.
The AFFIRM-AHF trial recently showed intravenous FCM treatment reduced the risk of HF hospitalization and improved quality of life (QoL) compared with placebo in patients with iron deficiency who had been stabilized after an AHF episode . However, FCM had no significant effect on the composite primary endpoint of HF hospitalization and CV death.
Aim of the study
In a prespecified exploratory subgroup analysis of the AFFIRM-AHF trial, the authors investigated the effects of intravenous FCM compared with placebo on clinical and QoL outcomes in iron-deficient patients with baseline hemoglobin values <12 g/dL versus ≥12 g/dL after stabilization following an AHF episode.
The AFFIRM-AHF trial was an international, multicenter, double-blind, placebo-controlled, phase 4 RCT in which 1108 patients hospitalized with signs and symptoms typical of AHF who had LVEF <50% and concomitant iron deficiency were randomized to intravenous FCM or placebo administered shortly before hospital discharge and for up to 24 weeks thereafter. Iron deficiency was defined as serum ferritin <100 μg/L, or serum ferritin 100–299 μg/L with transferrin saturation (TSAT) <20%. Patients with hemoglobin >15 g/dL were excluded.
In this subgroup analysis, 1107 patients with a baseline hemoglobin measurement were included: 464 patients in the subgroup with low hemoglobin levels (i.e., <12 g/dL; 228 treated with FCM and 236 with placebo) and 643 in the subgroup with normal hemoglobin levels (i.e., ≥12 g/dL; 329 treated with FCM and 314 with placebo).
The primary endpoint was a composite outcome of total HF hospitalizations and CV death up to 52 weeks. Secondary endpoints included a composite outcome of total CV hospitalizations and CV death; time to CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalization or CV death.
Additional outcomes were, among others, changes in disease-specific QoL assessed using the self-administered 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), hemoglobin, serum ferritin, and TSAT levels, and adverse events.
Primary and secondary endpoints
- In the subgroup with low hemoglobin, the annualized event rate for the primary endpoint was 71.1 per 100 patient-years for patients treated with FCM and 73.6 per 100 patient-years for those on placebo (rate ratio (RR): 0.97; 95%CI: 0.66–1.41). In the normal hemoglobin subgroup, this event rate was 48.5 and 72.9 per 100 patient-years, respectively (RR: 0.67; 95%CI: 0.48–0.93).
- No significant interaction between hemoglobin subgroup and treatment effect was observed for the primary endpoint (P for interaction=0.15).
- For the secondary endpoints, there were also no differences in the annualized event rates between patients treated with FCM or placebo within the 2 hemoglobin subgroups, nor were there any significant interactions between hemoglobin subgroup and treatment effect.
- Post-hoc sensitivity analyses using the World Health Organization’s definition of anemia (hemoglobin <12 g/dL for women and <13 g/dL for men) yielded similar results as the main analysis, as did a priori–defined pre–COVID-19 pandemic sensitivity analyses.
- Adjusted mean changes from baseline in KCCQ-12 overall summary score (OSS) and clinical summary score (CSS) were numerically greater in FCM-treated patients versus placebo-treated patients between weeks 2 and 52 in the normal hemoglobin subgroup (reaching statistical significance at weeks 4 and 6 (OSS and CSS) and 12 (OSS only)) and between weeks 6 and 24 in the low hemoglobin subgroup (no statistical significance).
- Significantly greater mean changes from baseline in hemoglobin, serum ferritin, and TSAT levels were seen with FCM versus placebo between weeks 6 and 52 in both the low and normal hemoglobin subgroups (all P≤0.05).
- In both hemoglobin subgroups, comparable rates of treatment-emergent adverse events were observed in the FCM and placebo arms (ranging from 62% to 68%), leading to premature study discontinuation in approximately 20% of the patients (low hemoglobin subgroup) and about 16% of the patients (normal hemoglobin subgroup).
In this prespecified exploratory subgroup analysis of the AFFIRM-AHF trial in patients with iron deficiency who had been stabilized after an AHF episode, no significant interaction between hemoglobin subgroup (<12 vs. ≥12 g/dL) and the effect of treatment with intravenous FCM versus placebo was observed for the composite primary endpoint of HF hospitalization and CV death or any of the related secondary endpoints . FCM improved several iron parameters over time in both hemoglobin subgroups and also improved QoL in the second month in the group with normal hemoglobin levels .
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