Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure) trial
EHJ Aug 2014
SOURCES OF FUNDING: The study was sponsored by Vifor Pharma Ltd., Glattbrugg, Switzerland.

CHF patients with Iron Deficiency Anemia can experience significant and sustainable improvements in functional capacity and quality of life as well as
reduced risk of hospital admission for worsening heart failure by receiving just one to two intravenous doses of an iron supplement
“Iron deficiency has recently been reported as a frequent co-morbidity in heart failure and has been associated with impaired functional capacity, poor
quality of life, and increased mortality, irrespective of the presence of anaemia. Therefore, correction of iron deficiency itself should be considered an
attractive therapeutic target in this population.”
CONFIRM-HF was a double-blind, placebo-controlled trial, which enrolled 304 stable, symptomatic heart failure patients from 41 sites across nine
European countries.

All patients had iron deficiency, defined as a serum ferritin level of less than 100 ng/mL, or between 100 and 300 ng/mL if transferrin saturation
[TSAT] was less than 20%.

Subjects were randomised to receive either intravenous iron (n=152), given as ferric carboxymaltose solution (FCM), or a normal saline placebo
(n=152), for 52 weeks. In the FCM arm, the median total dose was 1500 mg of iron during the one year study period (ranging from 500 to 3500 mg of
iron). Over 75% of the patients required a maximum of two injections of FCM to correct and maintain the iron parameters.

Completion of the six-minute walk test (6MWT) was required at baseline, and the primary endpoint of the study was improvement in this test at week
Dosing with FCM compared to placebo resulted in a significant increase in the distance subjects completed during the 6MWT.
Specifically, compared to placebo-treated subjects, those treated with FCM completed 33 extra metres in the 6MWT at week 24 (p=0.002), 42 extra
metres at week 36, and 36 extra metres at week 52 (both p<0.001).
Importantly, improvement in the 6MWT distance was seen across all subgroups, including patients with and without anaemia, “which further challenges
the traditional view linking adverse consequences of iron depletion with anaemia,” he added. “Iron depletion impedes oxygen transportation and
utilisation and so we expected that targeting this depletion would improve patients’ exercise tolerance.”
The study also showed concomitant improvement in other measures of functional status and quality of life among those treated with FCM compared to

From week 12 onwards, the FCM-treated subjects showed a significant benefit in Patient Global Assessment compared with placebo (p= 0.035 at
week 12, p=0.047 at week 24 and p<0.001 at weeks 36 and 52), and there was a similar pattern seen in improved New York Heart Association class
(p= 0.004 at week 24 and p< 0.001 at weeks 36 and 52).

Fatigue scores were also significantly improved in the FCM compared to placebo-treated subjects, as were quality of life scores on both the Kansas
City Cardiomyopathy Questionnaire [KCCQ] and European Quality of Life 5D [EQ-5D] questionnaire.
Importantly, compared to placebo, treatment with FCM was also associated with a significant 61% reduction in the risk of hospitalisation due to
worsening heart failure (hazard ratio [HR] 0.39; p=0.009).
“Hospitalisations due to heart failure are an economic burden for society, resulting in poor outcomes and impaired quality of life for patients.  There is
evident need for their prevention. In this context the results of CONFIRM-HF are of particular interest. Among recently introduced pharmacological
therapies only ivabradine has demonstrated such results,”
Despite the reduction in hospitalisations among FCM-treated patients, the number of deaths was similar in both groups, suggesting a one-year follow-
up may not be long enough to detect differences in mortality
Current ESC guidelines for managing heart failure patients recognise iron deficiency as a common and clinically relevant comorbidity which should
always be tested for. However at the same time, there is a relatively weak recommendation to manage iron deficiency in such patients, mainly because
of a paucity of evidence confirming the benefits of iron repletion. For a stronger recommendation of iron depletion as a valid therapeutic target in
heart failure, well-designed and controlled studies with adequate follow-up are needed. CONFIRM-HF was designed and executed with this goal

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 ( number NCT01453608).