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Iron supplementation maintains exercise capacity in heart failure with iron deficiency
Literature - van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. - Circulation. 2017; published online ahead of print


Up to 35-50% of heart failure (HF) patients have iron deficiency, which is associated with the severity of the disease, and is a strong and independent predictor of outcomes [1-3]. Studies showed that the administration of the intravenous (IV) iron agent ferric carboxymaltose (FCM) improved symptoms, outcomes, quality of life, and functional capacity measured with the 6 minutes walking test, irrespective of the presence of anemia [4,5].

In this prospective, randomized, controlled, multi-center, open-label trial, with blinded end-point evaluation, the effect of treatment with IV FCM on exercise capacity was assessed compared to standard of care, in patients with symptomatic chronic HF and iron deficiency.

Eligible patients had NYHA functional class II-III, left ventricle ejection fraction (LVEF) ≤45%, BNP >100 pg/mL and/or NT-proBNP >400 pg/mL, a VO2 of 10-20 mL/kg/min, serum ferritin<100 ng/mL or a serum ferritin of 100-300 ng/mL plus a transferrin saturation (TSAT) <20%, and were on optimal background therapy for HF for at least 4 weeks with no dose changes in the last 2 weeks.

After an initial screening period (up to 12 weeks) eligible subjects were randomized (1:1) to FCM or usual care for a period of 24 weeks. Dosing at day 0 and week 6 was based on screening hemoglobin (Hb) and weight, and not on ferritin and TSAT results. For patients in the standard of care group, oral iron was allowed.

The primary endpoint was the change in peak VO2 from baseline to 24 weeks. For the primary analysis, patients who died had a value of zero imputed for 24-week peak VO2. Secondary endpoints included the effect of FCM on hematinic indices (Hb, ferritin, and TSAT), natriuretic peptides (BNP and NTproBNP), NYHA functional class, and patient global assessment (PGA). In addition, safety parameters were collected.

Main results

  • Of the 86 patients in the FCM group, 42% received only one administration, 55% needed two and in only three patients (3%), three administrations were required. The mean administered dose of FCM was 1204±391 mg (median dose 1000 mg).
  • After 24 weeks all hematinic indices had increased significantly in the FCM group: Hb was 13.9±1.3 g/dL, ferritin was 283±150 ng/mL and TSAT was 27±8% (all P<0.05 compared to baseline). All changes differed significantly vs. the standard of care group (P<0.05).
  • After 24 weeks, peak VO2 had decreased by 1.19±0.389 mL/min/kg in the control group, while it was virtually unchanged in the FCM group (-0.16±0.387 mL/kg/min) (least means of the difference ± SE: 1.04±0.44 ml/kg/min; P=0.02 between groups). Without imputation of deaths, peak VO2 at 24 weeks decreased by 0.63±0.375 mL/min/kg in the control group (least means of the difference 0.48±0.398 ml/kg/min; P=0.23 between groups).
  • Patients with anemia (Hb <12 g/dL) did not benefit more from FCM, than those without anemia (P-interaction: 0.758), and in the group of patients treated with FCM, there was no association between the change in Hb and the change in peak VO2 (for FCM: r=-0.0758; P=0.51).
  • 11 Patients in the FCM group had a HF hospitalization, and there were no deaths. In the standard of care group, 4 patients died during the study, 5 patients were hospitalized for worsening HF, and one more patient had a cardiac arrest at home with documented ventricular fibrillation, for which he later received an ICD. None of the hospitalizations were considered to be related to the study drug administration by the attending physician.
  • After 6, 12 and 24 weeks, patients on FCM had improved their NYHA functional class significantly as compared to control patients (with imputation; all differences P< 0.05).
  • PGA was also favorably affected by FCM as compared to placebo. This difference became evident at 12 and 24 weeks (with imputation; P<0.05 between groups).
  • No significant effect of FCM on BNP compared to usual care was observed.
  • FCM was generally well tolerated.


In patients with chronic HF and iron deficiency, IV iron supplementation with FCM had a beneficial effect on peak VO2 compared to standard of care treatment, irrespective of the presence of baseline anemia. Moreover, FCM led to repletion of iron stores and improvement in measures of disease severity and quality of life.


1. Van Veldhuisen DJ, Anker SD, Ponikowski P, et al. Anaemia and iron deficiency in heart failure: mechanisms and therapeutic applications. Nat Rev Cardiol 2011; 8: 485-493.

2. Klip IJT, Comin Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013; 165: 575-582.e3.

3. Cleland JG, Zhang J, Pellicori P, et al. Prevalance and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure. JAMA Cardiol 2016; 1: 539-547.

4. Anker SD, Comin Colet J, Filippatos G, et al, for the FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. New Engl J Med 2009; 361: 2436-2448.

5. Ponikowski P, Van Veldhuisen DJ, Comin-Colet-J, et al, for the CONFIRM-HF Investigators. Beneficial effects of longterm intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015; 36: 657-668.

Find this article online at Circulation

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