NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.

Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.

Many physicians with iron deficiency in HFrEF on their radar have been prescribing oral iron in affected patients on the grounds that it’s inexpensive, readily available, and perhaps could help. But its clinical utility was untested until Gregory D. Lewis, MD, presented the results of the IRONOUT HF trial at the AHA scientific sessions. And IRONOUT HF showed the therapy to be unequivocally without benefit.

The IRONOUT HF (Oral Iron Repletion Effects on Oxygen UpTake in Heart Failure) trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted by the National Heart, Lung, and Blood Institute’s Clinical Heart Failure Network investigators. It included 225 patients with HFrEF and iron deficiency who were randomized to 16 weeks of oral iron polysaccharide at 150 mg b.i.d. or matching placebo.

The primary endpoint was change from baseline to 16 weeks in exercise capacity, as measured via peak oxygen uptake during cardiopulmonary exercise testing. The results were no better in the iron-supplemented group than in placebo-treated controls. Nor was there any benefit for oral iron therapy in terms of quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire or any of numerous other secondary endpoints, according to Dr. Lewis, head of the heart failure section and director of the cardiopulmonary exercise testing laboratory at Massachusetts General Hospital, Boston.

Participants’ mean baseline hemoglobin level was 12.6 g/dL, but whether patients were anemic at baseline or not made no difference in terms of outcomes. Rates of venous congestion and bleeding were low during the trial.

The problem, the investigators found, was that high-dose oral iron only minimally repleted iron stores. Transferrin saturation increased by a paltry absolute 3% after 16 weeks of twice-daily therapy. Serum ferritin levels increased only 1/20th as much as after intravenous iron ferric carboxymaltose therapy in the earlier positive FAIR-HF (Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (N Engl J Med. 2009 Dec 17;361:2436-48).

Levels of hepcidin were elevated in study participants. And the higher the level of hepcidin – which Dr. Lewis called “a massive regulator of iron bioavailability and absorption” – the more refractory patients were to oral iron repletion.

Discussant Stefan D. Anker, MD, expanded on this point. Hepcidin regulates iron entry into the body via the gut. If the hepcidin level is elevated because of systemic inflammation, it will deny entry to iron by upregulating ferroportin or direct the iron to be sequestered in macrophages.

“Hepcidin was invented by nature to protect against iron from stimulating growth of bacteria. And when it’s elevated, taking iron orally just has no chance of success,” explained Dr. Anker, professor of cardiology at the University of Gottingen (Germany).

Dr. Anker, who chaired the positive FAIR-HF trial of intravenous iron, said IRONOUT HF was a very well-conducted and definitive clinical trial of oral iron supplementation in HFrEF.

“It’s very simple: Oral iron does not work in patients with chronic heart failure. That’s the take home message. It’s true for peak VO_{2 [oxygen consumption]}, for 6-minute walk distance, for symptoms, for quality of life, and even for surrogate markers like NT-proBNP [N-terminal pro b-type natriuretic peptide]. If iron doesn’t get into the body, it’s really difficult to [imagine] that the iron that doesn’t get into the body can exert an effect,” he said.

At the same late-breaking clinical trials session, Dirk J. van Veldhuisen, MD, presented the results of EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Iron Deficiency and Chronic Heart Failure), a multicenter European open-label trial in which 172 patients with HFrEF and iron deficiency were randomized to intravenous ferric carboxymaltose or standard therapy with no placebo control. Patients in the active treatment arm received on average 1,200 mg of ferric carboxymaltose dosed in two or three sessions 6 weeks apart.

The primary endpoint in EFFECT-HF was assessor-blinded change in peak VO₂ from baseline to week 24. The control group experienced a decrease in peak VO₂ over time such that there was a significant difference of 1.0 mL/kg per minute between the two groups.

The ferric carboxymaltose recipients also did significantly better in terms of secondary endpoints including improvement in New York Heart Association functional class, self-reported Patient Global Assessment score, and quality-of-life measures, reported Dr. van Veldhuisen, professor and chairman of cardiology at University Medical Center Groningen (the Netherlands).

Session moderator Clyde Yancy, MD, commented that intravenous iron is not ready for prime time use in clinical practice for several reasons. The open-label EFFECT-HF trial, like the earlier positive double-blind FAIR-HF and CONFIRM-HF IV ferric carboxymaltose trials, was too modest in size to be convincing, especially since this is an expensive and intrusive therapy.

“The endpoint of peak VO₂, although a very powerful endpoint, is still one for which there may be some subjectivity, and so we need a more definitive endpoint to be absolutely certain about the potential benefit of the administration of ferric carboxymaltose,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.

Discussant Adrian Hernandez, MD, of the Duke Clinical Research Institute in Durham, N.C., said he considers peak VO₂ an important endpoint.

“When you talk to patients, exercise capacity is an outcome that matters to them,” he said. “They often comment that what matters to them is living longer with a better quality of life, free of worsening heart failure, and having improvement in everyday functional status. So the cardiopulmonary exercise test is not just a surrogate endpoint; it’s a measure of functional outcome that matters to patients,” he said.

Still, like Dr. Yancy, Dr. Hernandez said he thinks it’s time to have larger, longer, definitive trials with clinical endpoints in order to understand the role of intravenous iron. Both cardiologists applauded Dr. Anker’s announcement that such a trial, known as FAIR-HF2, is now getting started.

The IRONOUT HF trial was funded by the National Institutes of Health. Dr. Lewis reported receiving research support from a handful of pharmaceutical and medical device companies. Dr. van Velduisen reported serving as a scientific adviser to Vifor Pharma, which sponsored the EFFECT-HF trial. Dr. Anker, who was an EFFECT-HF investigator, serves as a consultant to Vifor and several other companies. Dr. Hernandez was an IRONOUT HF investigator and reported receiving research grants from a handful of pharmaceutical companies.

bjancin@frontlinemedcom.com

Mixed findings on iron repletion in HF