Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency

Abstract

Background: Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO₂], an objective measure of exercise intolerance in HF, has not been examined.

Methods: We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO₂ from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO₂. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO₂ data.

Results: A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO₂ was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO₂ had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO₂ at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care.

Conclusions: Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO₂ was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO₂ among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562.

Keywords: exercise capacity; ferric carboxymaltose; heart failure; iron deficiency.

Figure 1.

Consort diagram of the EFFECT-HF study (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Iron Deficiency and Chronic Heart Failure). Enrollment, outcomes, and availability of peak VO₂ test during the study are depicted. FCM indicates ferric carboxymaltose; ITT, intention to treat; peak VO₂, peak oxygen consumption; PP, per protocol; and SoC, standard of care.

Figure 2.

Effect of peak VO₂ after 24 weeks. A, Effect of peak VO₂ after 24 weeks in the whole (FAS) population. Left, LOCF (primary end point) is shown. Right, observed values (sensitivity analysis) are shown. B, Effect of peak VO₂ after 24 weeks in the PP population. Left, LOCF (secondary end point) is shown. Right, observed values (sensitivity analysis) are shown. FAS indicates full analysis set; FCM, ferric carboxymaltose; LOCF, last observation carried forward; LSM, least square means; peak VO₂, peak oxygen consumption; PP, per protocol; and SoC, standard of care.