Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: A pilot study

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Abstract

Background

Pulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency.

Methods

20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤ 1000 mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose.

Results

In iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7 ± 0.4 to 11.1 ± 1.1 μmol/L, ferritin 29.3 ± 6.3 to 145.2 ± 25.4 μg/L, transferrin saturation 7.5 ± 0.7 to 19.3 ± 2.3%, all p  0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5 ± 28.3 to 374.0 ± 25.5 m (p = 0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9 ± 25.3 to 379.6 ± 26.2 m; n.s.), resulting in a net increase in the 6MWD of 37.8 m (p = 0.003). This was associated with an improvement in QoL (SF-36 score from 44.3 ± 3.7 to 50.6 ± 3.6; p = 0.01). Only minimal side-effects were reported.

Conclusions

These data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.

Introduction

Pulmonary arterial hypertension (PAH) is a hemodynamic and pathophysiological condition defined by an increased mean pulmonary arterial pressure (PAP) of ≥ 25 mm Hg and normal pulmonary arterial wedge pressure (PAWP ≤ 15 mm Hg) at rest as assessed by right heart catheterization [1], [2]. In most cases, it is associated with a progressive increase in pulmonary vascular resistance (PVR) [1], [3], followed by right ventricular failure and, ultimately, death. Despite major improvements in targeted drug treatments, PAH remains a devastating condition with limited survival [4], [5], [6].

In addition to targeted drug therapies, current guidelines also recommend supportive treatments including the use of diuretics, supplemental oxygen, and anticoagulation [1], [7]. Recent studies have indicated that the presence of anemia and iron deficiency is common in patients with PAH and correlates with disease severity, exercise capacity and even survival [8]. In various cohorts, the prevalence of iron deficiency, defined by reduced serum iron and transferrin saturations, was recently reported between 28 and 50% in idiopathic PAH (IPAH) and up to 60% in heritable PAH (HPAH) [9], [10]. When iron deficiency was determined by the levels of circulating soluble transferrin receptor (sTfR), Rhodes et al. found iron deficiency without overt anemia to be present in even 63% of patients with IPAH [11]. Although it was reported that increased red cell distribution width (RDW), indicative of iron-deficiency anemia, or anemia itself is associated with adverse outcome in PAH [12], [13], the decreased exercise capacity seen in iron deficient patients compared to PAH patients with normal iron levels appeared to be independent of anemia [9]. Indeed, several studies indicate that iron deficiency alone is associated with a lower exercise capacity in PAH patients [9], [11], and represents an independent predictor of survival in PAH [11], [14]. In summary, these data highlight the high prevalence and clinical importance of iron deficiency in PAH and suggest that iron status may represent an important and accessible novel target for supportive therapeutic interventions.

While the FAIR-HF study has shown that restoring iron levels significantly improved quality of life, exercise capacity and New York Heart Association (NYHA) functional class in iron deficient patients with chronic left heart failure [15], the impact of iron supplementation in iron deficient patients with PAH and right heart failure has not yet been extensively studied. Interestingly, oral iron therapy was shown to be ineffective at restoring normal ferritin levels in the majority of PAH patients [9]. This may be explained by impaired dietary iron absorption, as PAH patients were recently shown to display increased levels of a key regulatory protein of iron homeostasis, hepcidin [16], which correlated with iron deficiency and impaired iron absorption from the gut [11]. We therefore assessed the efficacy, therapeutic potential and safety of intravenous iron supplementation with ferric carboxymaltose in patients with PAH and iron deficiency.

Section snippets

Study population

We prospectively investigated a series of twenty adult patients with symptomatic PAH (Nice group 1, as diagnosed by right heart catheter), who had significant iron deficiency (see below) and thus received iron supplementation. The results of the intervention group were compared to twenty matched control subjects with stable PAH of similar origin, but without iron deficiency, who did therefore not receive iron supplementation. Patients were matched for age, gender, type and duration of PAH, type

Ferric carboxymaltose profoundly improved iron status in PAH patients

Demographics, etiology of PAH, disease characteristics at baseline and targeted PAH therapy in the intervention and control groups are summarized in Table 1, Table 2.

PAH was of idiopathic or hereditary origin, or associated with connective tissue disease or corrected congenital heart disease (systemic-to-pulmonary shunts surgically repaired at least five years previously). All patients were in WHO functional class II or III, and were on stable doses of targeted PAH therapy with endothelin

Discussion

In the present pilot study, we show that parenteral iron supplementation with ferric carboxymaltose given as a single infusion was able to restore iron status, and improved exercise capacity and quality of life in patients with PAH and iron deficiency. This treatment was well tolerated and not associated with significant side effects. While iron deficiency was defined on the basis of laboratory markers (serum iron, serum ferritin and transferrin saturation) and iron-repletion dosages were

Conclusions

This open-label, matched-pair pilot study shows that intravenous iron supplementation with ferric carboxymaltose is well tolerated in iron deficient PAH patients and provides significant benefit on exercise capacity and quality of life, when given in addition to targeted PAH therapies. These benefits warrant further controlled studies to assess the value of iron as supplementary therapy for an extended population of PAH patients.

Acknowledgments

This work was supported in part by Vifor Pharma (Zürich, Switzerland). The company was not involved in study design, data collection or analyses. The technical support provided by Linda Esin (University of Cologne) and Susanne Rölle-Höhne (University of Cologne) is greatly appreciated and acknowledged.

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