Discussion
This study is the first clinical trial examining the effects of intravenous iron supplementation in patients with COPD. We found no impact of FCM on the primary outcome of oxygenation, but in common with clinical trials in patients with heart failure and idiopathic pulmonary hypertension, intravenous FCM produced statistically significant effects on exercise capacity and breathlessness-related functional limitation.
Iron status in COPD
One working definition of iron deficiency is ferritin <12 µg/L or transferrin saturation <16% or soluble transferrin receptor >28.1 nmol/L.15 25 By this definition, 10% of our participants were iron-deficient. An alternative definition of iron deficiency that has been used in patients with heart failure and idiopathic pulmonary hypertension is ferritin <100 µg/L or ferritin <300 µg/L with transferrin saturation <20%.7 26 Using this definition, 69% of our participants would have been classified as iron-deficient. The contrast between these two percentages illustrates the difficulty of defining iron deficiency, particularly in the presence of inflammation.25 Additionally, it is clear that intravenous iron has biological effects even in the absence of iron deficiency, as evidenced by the major effect of intravenous iron administration on pulmonary vascular responses to hypoxia in healthy volunteers.3–6 These considerations informed our decision to recruit patients with or without iron deficiency in the current trial.
Oxygenation
Iron has well-established effects on the pulmonary vascular responses to hypoxia.2–6 10 As such, it has been suggested that reduced iron availability may impair the matching of ventilation and perfusion in the lung and therefore reduce arterial oxygenation.15 27 This, coupled with a previous cross-sectional study that revealed an association between iron status and arterial hypoxaemia, informed our choice of arterial oxygenation as the primary outcome measure.15
The present study was powered to detect a 2% absolute rise in oxygen saturation after intravenous FCM. No such increase was identified in our study cohort. However, given that the mean oxygen saturation of the participants in this study at baseline (94.4%) was only marginally (<1%) lower than mean oxygen saturation for age-matched individuals from the general population,28 a significant improvement in oxygen saturation would have been very unlikely in our participants. It remains uncertain whether an effect of FCM on oxygen saturation would be detectable in a group of patients with more significant hypoxaemia at baseline.
Mechanism of improvement in 6MWD
In patients with COPD, 6MWD correlates with the ability to perform activities of daily living and is inversely associated with mortality.17 29 Although the within-group increase of 24 m seen in the FCM group is less than the minimal clinically important difference (30–40 m) in this setting,17 29 it is strikingly similar to the improvement seen at 8 weeks in the landmark trial of intravenous FCM in patients with heart failure.7 In that study, exercise capacity rose progressively over at least 12 weeks, with a mean increase of ≥35 m seen 12 weeks and 24 weeks after FCM. It is therefore possible that a longer duration of follow-up might reveal a greater effect of intravenous iron.
The literature provides a number of possible explanations for the effect of FCM on exercise capacity in our study participants. First, the pulmonary artery pressure during exercise is reduced for at least 8 weeks after FCM in healthy older adults.30 While this was not measured in the current study, exercise-induced pulmonary hypertension is common in COPD and may limit exercise capacity.12 31
Second, in patients with heart failure, the benefits of intravenous iron may result from correction of cardiomyocyte iron deficiency,9 32 even in the presence of normal systemic iron status. Heart failure is a common comorbidity in patients with COPD,33 raising the possibility that similar mechanisms could underlie the positive effects of intravenous iron in the current study.
Finally, skeletal muscle dysfunction is increasingly recognised as an important contributor to exercise limitation and functional limitation in COPD,34 35 and muscle function depends crucially on the availability of iron, through its central role in oxidative phosphorylation. Increased skeletal muscle iron availability has also been suggested as an explanation for the benefits of iron in patients with heart failure,35 and in keeping with an effect on muscle oxidative capacity, iron administration increases the time to anaerobic threshold during submaximal exercise in patients with pulmonary hypertension.8
MRC Dyspnoea Scale score
The improvement of MRC Dyspnoea Scale scores in the FCM group after 1 week is of particular interest, as lower scores are associated with increased survival.36 Furthermore, there are very few interventions in COPD that consistently improve this score.37 The disparity between the effect of FCM on the MRC scale and the lack of an effect on other symptom scores may arise because the former is not a direct measure of dyspnoea, but rather a function of the amount of physical activity required to induce breathlessness.37 Thus, the observed improvement in MRC score seems likely to reflect the improvement in 6MWD.
Safety profile of FCM
In other patient groups, FCM has a very favourable safety profile.38 In the current study, there was no excess of adverse events in the FCM group, compared with placebo, with the exception of hypophosphataemia, which is a well-documented side effect of FCM.38 Importantly, given the theoretical concern that increased iron availability may facilitate the growth of bacteria in the lungs,39 we did not identify any significant increase in the rate or severity of infective exacerbations of COPD, although over a relatively short time course of the current trial. Future studies will be needed to confirm this finding over a longer period of time.
Limitations
An important limitation of this preliminary trial is that the positive findings were limited to the secondary outcome measures. While this is of less concern in a first study to explore the potential benefits of intravenous iron in COPD, it nevertheless emphasises the need for further clinical trials in which an exercise-related variable is chosen as the primary outcome measure. This study is also a small single-centre study, which inevitably limits the degree to which its findings can be translated to a more general COPD population.
A further limitation of the current study is the lack of characterisation of the pulmonary vascular effects other than in a small subset of patients. Understanding the effects of intravenous iron on pulmonary artery pressures might have important implications for the targeting of iron therapy to specific populations of patients with COPD, for example those with known exercise-induced pulmonary hypertension or comorbid heart failure.
Conclusions
In summary, in this preliminary randomised controlled trial, intravenous FCM had no effect on SpO2. It was, however, associated with small but significant improvements in exercise performance and functional status in non-anaemic patients with COPD. Intravenous iron is well tolerated, widely available and inexpensive. COPD is characterised by a very substantial symptom burden and a relative scarcity of effective interventions. If our findings are confirmed in future trials, intravenous iron could become an important therapeutic option in the management of this condition.