The FERRIC-HF (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure), FAIR-HF (Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency) and CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure) trials investigated the safety and efficacy of IV iron in patients with heart failure and iron deficiency (ferritin <100 μg/L or <300 μg/L and transferrin saturations <20%).73,80,81
In FERRIC-HF, 35 patients were randomised in a 2:1 ratio to either placebo or IV iron, which was given weekly for four weeks and then at four-weekly intervals for 16 weeks. The iron dose was based on body weight and baseline haemoglobin. The primary end point was a change in peak VO2 (considered the gold standard measure of exercise capacity in patients with heart failure) from baseline to 18 weeks.
Despite a significant increase in ferritin levels and transferrin saturations in the iron group, there was no significant difference in peak VO2 after 18 weeks of treatment with IV iron compared with placebo (P=0.08). However, the investigators reported a small but significant change in peak VO2 adjusted for body weight (treatment effect +2.2 ml/kg/min, P=0.01), a variable that may predict risk of mortality more accurately than peak VO2 in patients with chronic heart failure.82 Adverse event rates were similar between the iron and placebo groups and no event was identified as being related to the treatment.
In FAIR-HF, 459 patients were randomised in a 2:1 ratio to either IV iron or placebo (average age 67 years, average LVEF 31%, approximately 80% of whom were NYHA class III). Iron was given weekly until iron stores were normal and then every four weeks for a total of 24 weeks. The primary end point was a change in patient-reported symptoms or NYHA class.
50% of patients in the iron group reported that their symptoms were ‘moderately’ or ‘much’ improved compared to 28% of patients in the placebo group (p <0.001). IV iron was also associated with an improvement in NYHA class (odds ratio for improvement by one class was 2.40, P<0.001 compared to placebo).
There were significant improvements in secondary end points, including 6MWT distance and QoL scores in the IV iron group compared with placebo (p <0.001). In pre-planned subgroup analysis, IV iron was as effective for patients without anaemia (Hb ≥12 g/dL) as it was for patients with low haemoglobin levels.83
Rates of death, hospitalisation and non-serious adverse events were similar in both groups and injection site discolouration or pain was reported in six patients in the IV iron group – no patient had an allergic reaction to the treatment.
In CONFIRM-HF, 301 patients were randomised to either IV iron or placebo (average age 69 years, average LVEF 37%, NYHA class II or III, average NTproBNP 2511 pg/mL in the iron group). Iron stores were replaced in an initial six-week treatment phase followed by further iron infusions every 12 weeks only if the patient was still iron deficient. The primary outcome was change in 6MWT distance after 24 weeks of treatment, with follow up continued to one year.
6MWT distance increased on average by 18 metres in the iron group and reduced by 16 metres in the placebo group giving a difference in the change in 6MWT distance of 33 metres (p = 0.002). NYHA class, patient-reported symptoms and QoL measures all improved significantly after 24 weeks of treatment with changes sustained to one year.
Mortality rate was similar between the groups but more patients were hospitalised in the placebo group compared to the iron group (29% vs. 21%). Treatment with IV iron was associated with reduced risk of hospitalisation with HF compared to placebo (HR 0.39, P=0.009).
In post-hoc analysis, IV iron was associated with reduced risk of a composite outcome of risk of hospitalisation with heart failure or all-cause mortality compared with placebo (HR 0.53, p = 0.03). As with the results of FAIR-HF, IV iron was beneficial regardless of whether or not the patients were anaemic (Hb ≤12 g/dL).
There were 14 drug-related adverse events in the iron group compared to five in the placebo group. One patient randomised to iron was withdrawn from the trial following a drug-related adverse event; no patients taking placebo were withdrawn.
CONFIRM-HF demonstrated a less-intensive but equally effective treatment regimen for IV iron in patients with heart failure and iron deficiency compared to that used in FAIR-HF. It also showed that improvements in exercise capacity and symptoms can be maintained beyond the initial treatment period. Furthermore, it hinted at the possibility of treatment with IV iron reducing the risk of adverse outcome, albeit with small numbers and a low event rate.
Subsequent individual patient data meta-analysis of both trials has found that treatment with IV iron reduces the rate of recurrent hospitalisation with heart failure (risk ratio [RR] 0.41, p = 0.003) and rate of hospitalisation with heart failure or all-cause mortality (RR 0.54, p = 0.011).84
A large randomised, controlled trial with hard outcomes is yet to be undertaken. IRONMAN (Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency study) (NCT02642562) will investigate the effects of IV iron on cardiovascular mortality or hospitalisation with heart failure in patients with heart failure and iron deficiency (transferrin saturations <20% and/or ferritin <100 μg/L).
Despite the simplified treatment protocol demonstrate in CONFIRM-HF, regular IV iron infusions are expensive and logistically challenging. Iron tablets are cheap and widely available yet were not investigated for the treatment of iron deficiency in patients with heart failure until 2016.
The IRONOUT (Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure) study investigated the effect of high dose oral iron in patients with NYHA class II or III heart failure and iron deficiency (ferritin <100 μg/L or <300 μg/L and transferrin saturations <20%, average age 63 years, median LVEF 25%, median NTproBNP 1,111 pg/mL, median Hb 12.6 g/dL). Some 225 patients were randomised to either iron polysaccharide 150 mg twice daily or placebo for 16 weeks. The primary outcome was the change in peak exercise oxygen uptake (peak VO2), secondary outcome measures included other exercise variables, 6MWT distance, NTproBNP levels and QoL measures.
Peak VO2 increased in the oral iron group but there was no significant difference in the change of peak VO2 between the oral iron group and placebo groups. The treatment with oral iron had no effect on other exercise variables, 6MWT distance, NTproBNP, or QoL measures. Adverse and serious adverse event rate and rate of study drug discontinuation were similar between the groups.
While transferrin saturations significantly improved (p = 0.003), the median increment from baseline at 16 weeks for patients treated with oral iron versus placebo was very small (3%). Such small improvements were unlikely to result in changes in exercise capacity particularly when compared to the changes seen in FAIR-HF (70% median-increment in transferrin saturations).78
Ultimately, despite 16 weeks of treatment, the patients in the oral iron group remained iron deficient (median ferritin 95 ng/L) – perhaps explaining the neutral findings. It is possible the duration and dose of treatment was insufficient to improve iron stores. Equally, it may be impossible to adequately treat iron deficiency in patients with HF with oral iron alone.