Iron Therapy in Patients With Heart Failure and Iron Deficiency

Review of Iron Preparations for Practitioners

Marcin Drozd; Ewa A. Jankowska; Waldemar Banasiak; Piotr Ponikowski


Am J Cardiovasc Drugs. 2017;17(3):183-201. 

In This Article

Is It Worthwhile to Treat ID in HF?

The benefits of iron replenishment have been tested in a few studies. Most of these studies have been performed in small subgroups, and the value of this data is limited. Taking into consideration all the evidence, the therapeutic effect of iron supplementation involves an improvement in (a) exercise capacity {increase in 6MWT distance[12,13,93–95,101] and higher peak VO2 in cardiopulmonary exercise testing (only anaemic patients have been tested)[96]}, (b) HF symptoms (NYHA class[12,13,95–97,101] fatigue score[12,96]), and (c) HRQoL {as assessed using different questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ) score and EuroQol five dimensions questionnaire (EQ-5D) health state score,[12,13] MLHFQ score,[94–97] linear analogue scale assessment (LASA),[103] and self-reported patient global assessment (PGA)[12,13,96]} (Table 5).

In small samples (treated groups: n = 16, n = 20, n = 24, n = 22, n = 30), an improvement in echocardiographic parameters has been observed, but only in anaemic patients (Table 5).[94–97,101] Currently, it is being verified in patients with ID and HF (NYHA II–III) with left ventricular ejection fraction (LVEF) of ≤45% whether treatment with FCM improves LVEF as determined by cardiac magnetic resonance imaging from baseline to week 12 ( iCHF, NCT01837082).

The results of smaller studies are consistent with the results of two large, multicentre, randomized, double-blind, placebo-controlled trials, in which iron therapy improved primary outcomes: NYHA class and self-reported PGA in the FAIR-HF trial[13] and 6MWT distance in the CONFIRM-HF trial.[12] In the FAIR-HF trial, 304 ambulatory symptomatic HF patients [LVEF ≤40% (NYHA II) or ≤45% (NYHA III)] with ID (serum ferritin <100 ng/mL or ferritin 100–300 ng/mL with TSAT <20%) and haemoglobin 9.5–13.5 g/dL were randomized in a 2:1 ratio to receive 200 mg FCM IV or saline IV weekly until iron repletion (the correction phase), then monthly until week 24 (the maintenance phase). Primary endpoints were self-reported PGA at week 24 and NYHA class at week 24, adjusted for baseline NYHA class.[43] Among patients receiving IV iron, 50% were reported as being much or moderately improved, as compared with 28% of subjects receiving placebo, according to the self-reported PGA. Among patients assigned to FCM, 47% had an NYHA functional class of I or II at week 24, as compared with 30% of study participants assigned to placebo. Significant improvements were also seen with the iron arm in 6MWT distance and quality of life. The results were similar in patients with and without anaemia, and it is worth noting that iron therapy improved HF symptoms even without a significant change in haemoglobin concentration from baseline. The rates of death, adverse events, and serious adverse events were similar in two study arms.[13]

In the CONFIRM-HF trial, ambulatory patients with HF [NYHA class II/III, LVEF ≤45%, brain natriuretic peptide (BNP) >100 pg/mL or NT-proBNP >400 pg/mL], ID (definition analogous to the FAIR-HF trial),[12] and haemoglobin below 15 g/dL were randomized 1:1 to treatment with FCM or placebo for 52 weeks. The dosing scheme is presented in Table 3. Study medication was administered in single doses as undiluted bolus injection of up to 1000 mg of iron or normal saline at day 0 and week 6 up to iron repletion. Further doses of FCM were administered at weeks 12, 24, and 36—if predefined ID was still present.[128] The primary endpoint was a change from baseline in 6MWT distance at week 24. Secondary endpoints were change in PGA, NYHA class, fatigue score, and HRQoL. Treatment with FCM significantly improved 6MWT distance at week 24, with the treatment effect consistent in all study subgroups and present up to week 52. Throughout the study, an improvement in NYHA class, PGA, HRQoL, and fatigue score in patients treated with FCM was detected, with statistical significance observed from week 24 onwards. The number of deaths (FCM 12, placebo 14) and the incidence of adverse events were comparable between the two study groups (iron vs. placebo).[12] Importantly, in post hoc sensitivity analyses, the treatment with FCM reduced the combined risk of first hospitalization for worsening HF or all-cause death.

There are a few meta-analysis regarding iron therapy in patients with HF and ID.[129–133] The most recent report analysed the results of five trials regarding HF patients with LVEF of ≤45% (509 patients received IV iron therapy, and were compared with 342 controls), with at least a single-blind randomization, and without a concomitant therapy with erythropoiesis-stimulating agents.[133] It has been shown that IV iron therapy reduced the risk of unplanned HF hospitalization, the risk of the combined endpoint of all-cause death or cardiovascular hospitalization, and the risk of combined cardiovascular death or hospitalization for worsening HF, but without the impact on either all-cause or cardiovascular mortality (which may be due to a low number of reported events and relatively short follow-up).[133] Additionally, iron therapy resulted in an improvement in exercise capacity, an alleviation of HF symptoms, and an improvement in HRQoL as assessed using questionnaires either specific for HF or those reflecting patients' general medical condition.[133]

At present, a new RCT is being conducted on a relatively large group of subjects and aims to verify the effect of FCM on exercise capacity (as a change in peak VO2 from baseline to week 24) in anaemic and non-anaemic iron deficient subjects with stable chronic HF (NYHA II–III) on optimal background therapy for heart failure with reduced exercise capacity and reduced LVEF ( EFFECT-HF, NCT01394562).

We would like to emphasize the fact that the IV iron administration differed in two major clinical trials in HF. In FAIR-HF, during the correction phase, patients received FCM IV infusion weekly. The total dose needed to correct ID was calculated according to Ganzoni's formula[112] and was provided over a period of between 3 and 7 weeks (a median of six injections). In CONRFIM-FH, the FCM was administered in large doses (500 mg or 1000 mg) based on subject weight and haemoglobin value at screening, according to the scheduled dosing scheme (Table 3). Over 75% of the patients required a maximum of two injections of FCM (with a 6-week interval) to correct and maintain the iron repletion. Based on the pharmacological characteristics of the drug, this treatment scheme is actually recommended.

It is also worthy of note that beneficial effects of IV iron treatment are encountered as early as 4 weeks after commencement of supplementation.[12,13]

Moreover, it has been shown that the treatment of ID with FCM in patients with chronic HF is equally efficacious across different clinical subgroups (NYHA class, 6MWT, PGA, KCCQ score and EQ-5D health state score) and shows a similar favourable safety profile, irrespective of the concomitance of anaemia.[113]

Based on aforementioned evidence, the 2016 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic HF emphasize the clinical relevance of predefined ID in HF patients regardless of haemoglobin level (and the presence of anaemia)[134] and recommend consideration of IV iron therapy in symptomatic patients with HFrEF and absolute or functional ID (serum ferritin <100 μg/L, or ferritin between 100–299 μg/L and TSAT <20%) in order to alleviate HF symptoms and improve exercise capacity and quality of life[134] (class of recommendations IIa, level of evidence A).