Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†

Abstract

Aim: The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF).

Methods and results: CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction ≤45%, elevated natriuretic peptides, and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%). Patients were randomized 1 : 1 to treatment with i.v. iron, as ferric carboxymaltose (FCM, n = 152) or placebo (saline, n = 152) for 52 weeks. The primary end-point was the change in 6-min-walk-test (6MWT) distance from baseline to Week 24. Secondary end-points included changes in New York Heart Association (NYHA) class, Patient Global Assessment (PGA), 6MWT distance, health-related quality of life (QoL), Fatigue Score at Weeks 6, 12, 24, 36, and 52 and the effect of FCM on the rate of hospitalization for worsening HF. Treatment with FCM significantly prolonged 6MWT distance at Week 24 (difference FCM vs. placebo: 33 ± 11 m, P = 0.002). The treatment effect of FCM was consistent in all subgroups and was sustained to Week 52 (difference FCM vs. placebo: 36 ± 11 m, P < 0.001). Throughout the study, an improvement in NYHA class, PGA, QoL, and Fatigue Score in patients treated with FCM was detected with statistical significance observed from Week 24 onwards. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [hazard ratio (95% confidence interval): 0.39 (0.19-0.82), P = 0.009]. The number of deaths (FCM: 12, placebo: 14 deaths) and the incidence of adverse events were comparable between both groups.

Conclusion: Treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF (ClinicalTrials.gov number NCT01453608).

Keywords: Ferric carboxymaltose; Heart failure; Iron deficiency.

Figure 1

Enrolment and outcomes. The full analysis set comprised all patients who received at least one dose of randomized treatment and attended at least one post-baseline visit. The safety population included all patients who received at least one dose of randomized treatment. Supportive analyses were performed using the per-protocol set (those subjects who participated in the trial included in the full-analysis set without major protocol violations).

Figure 2

Patient Global Assessment and NYHA Functional Class over Time (full-analysis set). The data presented are odds ratios for patient global assessment (A) and NYHA functional class (B) for the ferric carboxymaltose group when compared with the placebo, of being in a better category of patient global assessment (A) and NYHA functional class (B). In those panels, the P-values are for the comparison between the two study groups, and the I bars denote the 95% confidence intervals.

Figure 3

6-Min Walk Test, Fatigue and Quality of Life Score over Time (full-analysis set). Shown are data across the study period using a repeat measures model for the changes (least squares mean with the 95% confidence intervals on the 6-min walk test (A), Fatigue score (assessed using a 10-point visual analogue fatigue scale, ranging from 1 for no fatigue to 10 for very severe fatigue) shown in (B), Kansas City Cardiomyopathy questionnaire (KCCQ) score (on which the overall score ranges from 0 to 100, with a higher score indicating a better QoL) shown in (C), and the European Quality of Life-5 Dimensions (EQ-5D) Visual Analogue Scale (on which the score ranges from 0 to 100, with higher scores indicating better health) shown in (D).

Figure 4

Time to first hospitalization due to worsening heart failure. The time to first hospitalization due to worsening heart failure was estimated using the Kaplan–Meier method, on the full-analysis set. Subjects were censored at their death, study completion, or withdrawal date.

Figure 5

Subgroup analyses for 6-Min Walk Test. Shown are data of 6MWT distance change from baseline to Week 24 analysis results, using ANCOVA analyses with each subgroup as a covariate, and treatment and the interaction between treatment and subgroup as covariates. The least squares mean of the difference between ferric carboxymaltose and placebo groups and the 95% confidence intervals are displayed for each subgroup. The P-values of the interaction term (treatment and subgroups) are presented.