Intravenous IRON supplementation in Heart Failure with Preserved Ejection Fraction and iron deficiency (IRON-HFpEF): a comprehensive phase II multicentre placebo-controlled randomized clinical trial

Aims Iron deficiency (ID) is common in patients with heart failure with preserved ejection fraction (HFpEF). The IRON-HFpEF trial aimed to evaluate the mechanistic effects of intravenous iron supplementation on cardiovascular function and exercise tolerance in HFpEF.Methods 45 patients with HFpEF (LV ejection fraction >= 50%) and ID were recruited from Amsterdam UMC and Maastricht UMC+. Patients with ID-anaemia were excluded. Patients were randomized to receive either ferric carboxymaltose (FCM) or placebo. At baseline and 4 months, assessments included exercise right heart catheterization, 6-minute walking distance (6MWD), cardiac MRI, exercise calf muscle 31P-magnetic resonance spectroscopy, and laser speckle contrast analysis. There was also an open-label extension.Results Patients were in functional class II-III. FCM had no effect on pulmonary capillary wedge pressure during multiple levels of exercise (mean change -1.0 mmHg, 95% CI [-4, 2]; P = .52). FCM did not change myocardial PCr/ATP ratio (P = .18), calf muscle PCr recovery time (P = .11), NT-proBNP (P = .78), or Kansas City Cardiomyopathy Questionnaires (P = .67). However, FCM led to an improvement in right ventricular ejection fraction (FCM: +4 +/- 5% vs placebo: -3 +/- 6%; P = .002) and acetylcholine-mediated microvascular perfusion (FCM: +5 +/- 24 vs placebo: -16 +/- 25 a.u.; P = .04), and seemed to marginally improve 6MWD (+6 +/- 31 m vs -13 +/- 31 m; P = .06). After correction for baseline differences, FCM improved 6MWD (+28 m; P = .01).Conclusion In patients with HFpEF and ID without ID-anaemia, FCM did not improve exercise hemodynamics, LV diastolic function, myocardial or skeletal energy homeostasis. Exploratory analyses suggest that FCM does improve exercise tolerance (6MWD), potentially through improvement of microvascular endothelial function and RV function.