Patrice Wendling

November 18, 2016

NEW ORLEANS, LA — The issue of iron supplementation in patients with chronic heart failure remains unsettled after two new studies testing oral and intravenous iron yielded conflicting results at the American Heart Association 2016 Scientific Sessions.

Peak oxygen uptake (VO2) significantly improved when compared with standard of care after three intravenous injections of ferric carboxymaltose in HF patients with and without anemia in EFFECT-HF[1], while functional capacity and other outcomes failed to improve with a considerably cheaper oral iron supplement in the IRONOUT study[2].

Iron deficiency is present in about half of patients with chronic HF and is an independent predictor of mortality.

Invited discussant Dr Stefan Anker (University Medicine Göttingen, Germany) said IRONOUT was an excellent trial done by expert teams, but the simple conclusion is that oral iron does not work in HF.

"Almost all of these patients have a resistance to the uptake of iron" that seems to be mediated by hepcidin, and "if iron can't get into the body, you cannot expect it to work," he said.

Anker, who notably was also an EFFECT-HF investigator, said oral iron is given to thousands of patients with HF based on evidence from studies using intravenous iron. "This is not necessarily an evidence-based approach, and as you've seen now, it is an approach that may even be considered inappropriate."

Commenting on the overall findings, session moderator Dr Clyde Yancy (Northwestern University, Chicago, IL) noted to heartwire from Medscape that patients already have as a class IIa or class I indication at least seven individually unique medications for HF and at least three devices.

"The various permutations of 10 approved therapies for reduced-ejection-fraction heart failure has already complicated the space, incredibly so. So adding yet another parameter for an evidence-base that doesn't yet warrant moving forward is an important reason to pause," he said.

Intravenous Iron Delivers

The open-label EFFECT-HF study screened 525 symptomatic patients with NYHA class 2-3 HF, a left ventricular ejection fraction (LVEF) <45%, iron deficiency (serum ferritin <100 µg/L or 100–300 µg/L if transferrin saturation [TSAT] <20%) and hemoglobin <15 g/dL. A total of 174 patients who met study criteria and were able to do cardiopulmonary exercise testing were evenly randomized to IV ferric carboxymaltose (FCM) on day 0, week 6, and week 12 (mean treatment dose 1204 mg) or standard of care. In the IV-iron group, the mean baseline ferritin was 62.06 ng/mL and mean hemoglobin 12.93 g/dL.

The primary end point of change in peak VO2 at week 24 significantly improved with IV iron in the full data set (mean difference 1.04 mL/kg/min; P=0.02 for between-group difference) and in a per-protocol analysis of 146 patients (mean difference 1.32 mL/kg/min; P=0.01 for between-group difference).

The secondary end points of minute ventilation/carbon dioxide production slope and peak work rate were similar between groups, although IV iron significantly improved NYHA class and self-reported patient global assessment.

Dr Dirk van Veldhuisen

Lead investigator Dr Dirk van Veldhuisen (University of Groningen, the Netherlands) said the results confirm and extend those from FAIR-HF and CONFIRM-HF, two prior iron-repletion studies in which IV iron improved 6-minute-walk distance and quality of life and reduced HF hospitalizations.

EFFECT-HF discussant Dr Adrian Hernandez (Duke Clinical Research Institute, Durham, NC) questioned whether the trial represents a real-world population with the right outcomes, noting that screening out so many patients could lead to a biased population and that exercise capacity is an outcome that very much matters to patients.

Anker, who headed up FAIR-HF, told heartwire , "I'm not very concerned about these patients being or not being representative; it just shows the technical difficulties of this methodology when you apply it to sick, elderly patients."

That said, he pointed out that in the US intravenous iron is approved only for iron-deficiency anemia and the maximum approved dose is 750 mg, which means that more than half of patients in EFFECT-HF "are outside the US label."

Dr Gregory D Lewis

IRONOUT lead investigator Dr Gregory Lewis (Massachusetts General Hospital, Boston) said IV iron has shown benefits but that routine administration is expensive and poses logistical challenges.

They tested an oral iron polysaccharide 150 mg twice daily against placebo in 225 patients with NYHA class 2-4 symptoms and LVEF <40%. Mean ferritin was 69 ng/mL in both groups, and mean hemoglobin 12.6 g/dL in the oral-iron group and 12.7 g/dL in controls.

The treatment difference in change in peak VO2 at week 16 was not significantly different between groups in analyses with and without weight adjustment (21 mL/min, P=0.46; and 0.30 mL/kg/min, P=0.30).

Despite similar drug-discontinuation rates, the degree to which iron stores changed in response to oral iron was minimal. Ferritin levels and TSAT improved by only 11 ng/mL and 3%, respectively, and remained below the normal range. In contrast, IV iron in FAIR-HF resulted in a 20-fold greater increment in ferritin and fourfold greater increment in TSAT, Lewis said.

The investigators further looked at circulating levels of hepcidin, "the master regulator of iron bioavailability," and found "basically zero response to oral iron" in the two highest hepcidin quartiles. Higher baseline TSAT was modestly correlated with change in peak VO2 (r=0.17; P=0.03).

Lewis said the results cannot be explained by active venous congestion or bleeding and "do not support use of oral iron supplementation in patients with heart failure and reduced EF."

There was general agreement among experts that outcomes trials in HF patients are clearly needed, with FAIR-HF2 about to start.

Yancy told heartwire , "If there is a reproducible benefit and if the changes in functional capacity relate to clinical changes, then we have to understand what the real magnitude of that benefit is and then what the cost-effectiveness is of addressing that issue. Certainly a very cursory look at the retail cost for ferric carboxymaltose would suggest there is a significant cost involved."

EFFECT-HF was sponsored by Vifor Pharma. Van Veldhuisen reports receiving board membership fees and travel expenses from Vifor Pharma. Lewis reports research support from Abbott Vascular, Novartis, Stealth, and Shape Systems and consulting or advisory board participation for Ironwood. Anker reports consulting for Vifor, Luitpold, Novartis, Bayer, ASTRA, and Pfizer; grants from Vifor and Abbott Vascular; and being an investigator for EFFECT-HF and principal investigator for of FAIR-HF and FAIR-HF2.

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