Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure (FAIR-HF2-DZHK05) trial: Baseline characteristics and comparison to other relevant clinical trials

Introduction

Several modest to large scale clinical trials have evaluated the role of intravenous (IV) iron on outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) with concomitant iron deficiency (ID). Although earlier trials suggested a consistent benefit of IV iron in improving symptoms and functional status, and reducing HF hospitalizations in HFrEF,^1-3 more recent trials have been unable to replicate the same level of treatment benefit in larger cohorts of patients with chronic stable HFrEF.^{4, 5} These differences can be attributed to differences in IV iron dosing strategies, a lack of consistent IV iron administration during the maintenance phase following repletion of iron stores, slow enrolment and low adherence to therapy during the COVID-19 pandemic, low utilization of sodium–glucose cotransporter 2 (SGLT2) inhibitors, and the questionable appropriateness of the contemporary criteria for diagnosing ID in HFrEF.^6-8

The FAIR-HF2 (Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure) trial is designed to evaluate the efficacy of a more intensive and proactive regimen of IV iron (i.e. ferric carboxymaltose [FCM]) on clinical outcomes in patients with HFrEF. Herein, we describe the baseline characteristics of the FAIR-HF2 trial and compare them to baseline characteristics of patients enrolled in prior major trials of IV iron in HFrEF.

Methods

The design of the FAIR-HF2 trial has been described previously.⁹ Briefly, it is an international, double-blind, multicentre randomized controlled trial evaluating the efficacy of FCM versus placebo in patients with chronic HFrEF (left ventricular ejection fraction [LVEF] ≤45%) with concomitant ID. All patients were at least 18 years of age, have chronic HFrEF for at least 3 months with a documented LVEF ≤45%. Patients were also required to be eligible for discharge within 24 h if hospitalized with New York Heart Association (NYHA) class II or III symptoms, or ambulatory with NYHA class II–IV symptoms with a hospitalization for HF within the past 12 months. Key laboratory criteria for ID included a haemoglobin between 9.0 and 14.0 g/dl (in both, women and men), and the confirmed presence of ID defined as serum ferritin <100 ng/ml or between 100 ng/ml and 299 ng/ml (i.e. <300 ng/ml), if the transferrin saturation (TSAT) is <20%. The iron repletion protocol consisted of two phases; the repletion phase involved administration of 1000 to 2000 mg of FCM over 4 weeks followed by a maintenance phase which involved administration of 500 mg of FCM every 4 months until study end, with stopping criteria of haemoglobin >16 g/dl or serum ferritin >800 ng/ml. The trial has three co-primary endpoints: (i) time to first event of cardiovascular death or hospitalization for HF, (ii) the rate of total (first and recurrent) HF hospitalizations (both analysed in the full study population), and (iii) the time to first event of cardiovascular death or hospitalization for HF in patients with TSAT <20% at baseline.¹⁰

Results

A total of 1105 patients were randomized between March 2017 and November 2023 in 54 active sites from six countries. Baseline relevant clinical characteristics and HF-related characteristics are provided in Tables 1 and 2. The majority of patients were men (67%) and the median age was 72 (IQR 63–79). The median body mass index (kg/m²) was 27.5 (IQR 24.1–31.3). Most patients had either NYHA class II (66%) or class III symptoms (32%). Almost half the patients had diabetes mellitus (46%), atrial fibrillation/flutter (52%), and a prior myocardial infarction (48%); 79% had hypertension, 74% had coronary artery disease, and 67% had dyslipidaemia. More than one-third of patients (402 [36.4%]) had a hospitalization within the prior 12 months before enrolment. The median LVEF (%) was 35 (IQR 28–40), and the median eGFR was 58 (IQR 42–77) ml/min/1.73 m².

In FAIR-HF2, 78% of patients had ischaemic HFrEF which is similar to that observed in FAIR-HF (80%), whereas 57% patients in the IRONMAN trial, 60% in the HEART FID trial, and 47% in the AFFIRM-AHF trial were deemed to have ischaemic HFrEF. The mean LVEF was similar across the five trials. The distribution of other comorbidities was similar as shown in Table 3.

Discussion

We present details pertaining to the baseline characteristics of patients included in the FAIR-HF2 trial in comparison to past major IV iron trials in HFrEF and we present several key findings. The mean %TSAT is less than that observed in the HEART-FID trial, but largely similar to what was observed in the other four trials. There is also a much higher proportion of patients with ischaemic HFrEF, and those using SGLT2 inhibitors compared to prior trials (Graphical Abstract).

That the FAIR-HF2 population had relatively low %TSAT values at baseline (Figure 1) is important as lower values provide more certainty that truly iron-deficient patients were included. The recently suggested new and more simple definition of ID in HF relies on a TSAT cut-off of <20%. The rather high mean %TSAT of 22% at baseline amongst patients in the HEART-FID trial (median 23–24%),⁵ suggests that a substantial proportion of patients there may not have been truly deficient which may explain the suboptimal results found there. The FAIR-HF2 will include a primary endpoint that will compare the efficacy of IV iron in patients with TSAT <20% versus those with TSAT ≥20%. Evaluating the efficacy of IV iron is challenging due to several reasons. First, the criteria for defining ID have been scrutinized, with evidence suggesting little role of serum ferritin in defining ID, with %TSAT playing a much more central role, specifically in the identification of patients with functional ID.^{7, 12-14} This is important since accurate identification of ID would help recruit individuals that would potentially benefit most from IV iron repletion. Second, unlike other drugs used in HF, IV iron therapy has two phases to its administration which includes the initial repletion phase after initial diagnosis, followed by a maintenance phase after iron stores have been repleted.⁶ The dosing regimen for both these phases has not been standardized, especially for the latter where most patients enrolled in prior clinical trials did not receive any IV iron during the maintenance phase.^{6, 15} In the HEART-FID trial, only 20% of patients received IV FCM during the maintenance phase. The FAIR-HF employed a more aggressive approach toward repletion and maintenance of iron stores with an initial regimen of FCM 1000–2000 mg given during the repletion phase followed by FCM 500 mg given every 4 months to prevent transient depletion of iron stores, which may have affected results of prior studies.

Sodium–glucose cotransporter 2 inhibitors are the latest addition to guideline-directed medical therapy that improves outcomes in patients with HFrEF.^16-18 These drugs have also been shown to augment the haematological response to IV iron supplementation in patients with HFrEF.^{8, 19} On the other hand, they have also been shown to reduce levels of serum ferritin attributed largely to their anti-inflammatory effect rather than an effect on actual iron stores.^{19, 20} Given that the addition of SGLT2 to medical therapy regimen in HFrEF is very recent, prior trials have not had a sufficiently large number of patients on SGLT2 inhibitors, precluding an analysis of their effect on the efficacy of IV iron. Similarly, neprilysin inhibition is also associated with suppression of serum ferritin likely due to its anti-inflammatory effect similar to SGLT2 inhibitors.¹³ In FAIR-HF2, 23% of patients were using SGLT2 inhibitors and 38% were using ARNI therapy, which is still not optimal, but is likely sufficient for an exploratory analysis. On the contrary, a larger proportion of patients were on optimal guideline-directed medical therapy in FAIR-HF2 which may lead to lower cardiovascular events compared to prior trials.²¹ Moreover, a large proportion of patients in the FAIR-HF2 had ischaemic aetiology for their HFrEF (78%), which is similar to that observed in the FAIR-HF trial, whereas a much lower proportion of patients had ischaemic HFrEF in the AFFIRM-AHF, IRONMAN, and HEART-FID trials.^{1, 4, 5} Individuals with ischaemic HFrEF have significantly worse prognosis compared to those with non-ischaemic HFrEF and potentially derive a greater benefit from administration of IV iron.^{22, 23} Iron may in a beneficial way support cardiac metabolism that is deranged in HF, and possibly particularly so in patients with ischaemic disease aetiology.²³

The FAIR-HF2 trial recruited patients from Western and Eastern Europe with a predominantly White population included in the study, so the results of the study may not be globally generalizable to individuals of other races/ethnicities,²⁴ although there are limited data regarding variation in response to IV iron therapy based on patients' race/ethnicity. Most other demographics, including the proportion of women and clinical comorbidities, were similar across the four major IV iron trials.

In conclusion, the FAIR-HF2 trial is evaluating the efficacy of IV iron in patients with HFrEF and concomitant ID, and the baseline characteristics of enrolled participants largely resemble that of prior major IV iron trials except for a higher proportion of patients with ischaemic HFrEF and those using SGLT2 inhibitors and ARNI therapy.