FAIR-HF: Symptom Improvement, Functional Gains Follow Correction of Iron Deficiency in Heart Failure

November 18, 2009

November 18, 2009 (Orlando, Florida) — Patients with systolic heart failure and iron deficiency who were treated with the injectable iron preparation ferric carboxymaltose (Ferinject, Vifor Pharma) responded over 24 weeks with significantly improved symptoms, NYHA functional class, six-minute-walk distance, and quality of life, whether or not they also had anemia, in a randomized, placebo-controlled trial conducted primarily in Europe [1]. The treatment seemed well tolerated and didn't have a significant effect in either direction on clinical events.

That the iron-replacement therapy benefited the patients regardless of whether they had anemia at baseline "suggests that iron deficiency is a valid independent therapeutic target," write the study's authors, led by Dr Stefan D Anker (Charité Universitätsmedizin, Berlin, Germany), in their report published online today in the New England Journal of Medicine to coincide with release of their findings here at the American Heart Association (AHA) 2009 Scientific Sessions.

Iron levels in heart failure "have not been on our radar screen," observed Dr Mariell Jessup (University of Pennsylvania, Philadelphia) for heartwire . "I think anemia has been on our radar screen, and we've all been waiting for the trials using synthetic erythropoietin. But [iron-repletion therapy] has a lot of attractive aspects to it. Maybe anemia is the wrong surrogate."

At a news conference on FAIR-HF, Dr Marvin A Konstam (Tufts University, Boston MA), who isn't connected to the trial, agreed that it points to iron levels as a potential treatment target and that physicians with heart-failure patients should pay more attention to them. There has been more of a focus on the impact of anemia in that setting, he noted, and some think that correcting it is a worthwhile goal. "Many such patients who are anemic are also iron deficient--it's just fascinating to think that maybe the iron itself is a key therapeutic element."

Also at the press conference, Anker said his group has estimated that, depending on the definition of functional iron deficiency, it is present in about 20% to 30% of ambulatory patients with heart failure. If such patients are symptomatic, "physicians should [consider] iron deficiency. One can easily assess this using a blood test. If iron deficiency is present, give treatment with intravenous iron. And in this case, ferric carboxymaltose can be considered."

The study, called Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF), follows a series of recent smaller studies in which several forms of intravenous iron benefited patients with chronic heart failure, Anker et al note. It therefore solidifies an evidence base, one that has been expanding over the past three or four years, that points to a potential new treatment option for some patients with heart failure.

"Improvement in the quality of life is increasingly important to patients with heart failure, and the approach taken in this study may have merit in patients with moderately symptomatic heart failure and documented iron deficiency," writes Dr G William Dec (Massachusetts General Hospital, Boston) in an accompanying editorial [2]. Among several limitations of the trial, he notes, is a predominance of patients in NYHA class 3 (making it hard to apply the results to patients with "mild or advanced heart-failure symptoms") and subjective primary end points that are "less convincing than physiological variables such as submaximal or maximal exercise capacity."

Anker et al randomized 459 heart-failure patients in 11 countries who were in NYHA class 2 with an LVEF <40% or NYHA class 3 with an LVEF <45%, had an initial hemoglobin level of 95 g/L to 135 g/L, depressed serum ferritin levels, and no hepatic or renal dysfunction. They were assigned in a 2:1 ratio to receive either ferric carboxymaltose in IV doses each containing 200-mg iron or placebo; dosing was weekly for eight to 12 weeks (depending the patient's calculated iron deficit) and then every four weeks, for a total of 26 weeks of treatment.

The 304 patients in the iron-repletion group and the 155 controls were similar with respect to heart-failure severity, clinical features, cardiovascular risk factors, laboratory measurements (including those reflecting liver and renal function), and cardiovascular medications.

At week 24, 50% of patients in the iron-repletion group and 28% of controls reported that they were "much or moderately improved" on the Patient Global Assessment, a primary end point; the odds ratio (OR) for actively treated patients showing improvement compared with baseline was 2.51 (95% CI 1.75–3.61; p<0.001). Also at week 24, 47% and 30%, respectively, were in NYHA class 1 or 2, the trial's other primary end point; the OR for NYHA improvement by one class was 2.40 (95% CI 1.55–3.71; p<0.001) for iron-repletion patients.

Curves for the primary and secondary end points showed highly significant differences (p<0.001) between the groups even at four weeks or earlier.

As part of the panel discussion following Ankers formal FAIR-HF presentation, Dr Milton Packer (University of Texas Southwestern Medical Center) said, "One of the particularly intriguing things is the rapidity of the findings; the separation between the two treatments occurs so quickly. Even with what we think are accepted therapies for heart failure, the effect at four weeks is usually a fraction of what we see at eight weeks or 12 weeks. This is probably the fastest-acting separation that we've seen in a [heart-failure] clinical trial."

The benefits of iron therapy for the two primary end points were consistent in all subgroup analyses, including those by sex, age, renal function, NYHA class, LVEF, heart-failure etiology, diabetes status, and body-mass index, and most notably by hemoglobin level (<120 g/L, signifying anemia, vs >120 g/L) and median ferritin level (<39 µg/L vs >39 µg/L).

"In both groups [anemia and no anemia], the treatment was effective, and, interestingly, we observed that in the anemic patients there was an increase of hemoglobin of about 1 g/dL," Anker said. "There was no increase in hemoglobin at all in the nonanemic patients. So the improvement overall in symptoms and self-reported well-being seems to be related more to the fact that the patient received a correction of iron deficiency rather than a change in hemoglobin by this treatment."

At each of weeks 4, 12, and 24, patients receiving iron walked significantly farther on the six-minute-walk test and scored significantly better on the Kansas City Cardiomyopathy Questionnaire (p<0.001 for all differences).

Results of six-minute-walk test in meters, ferric carboxymaltose therapy vs placebo

Follow-up interval Iron-repletion therapy (m) Placebo (m) p
Baseline 274 269 NS
4 wk 294 269 <0.001
12 wk 312 272 <0.001
24 wk 313 277 <0.001

As the invited discussant following Anker's presentation, Dr Eldrin F Lewis (Brigham and Women's Hospital, Boston, MA) observed that "there was a dramatic change in the quality of life and exercise capacity within four weeks, suggesting that some of this benefit could be from enrollment in the clinical trial and the excellent care they received."

Still, he said, the iron therapy remains "a potential strategy for improving quality of life and exercise capacity, both of which [can be] markedly impaired in patients with anemia."

There were no significant differences in rates of death or of hospitalization for any cause, for any CV cause, for worsening heart failure, or in investigator-reported adverse events--except for adverse "cardiac disorders," which were more prevalent in the placebo group (p<0.01).

Anker and colleagues caution that their results apply only to the iron agent and dosing schedule studied and not to heart-failure patients with hemoglobin levels greater than 135 g/L.

Nevertheless, they write, "the study results suggest that in the assessment of ambulatory patients with symptomatic heart failure and systolic dysfunction, laboratory investigations to detect iron deficiency may be useful in routine practice to decide whether symptom management, by means of treatment with intravenous iron, is indicated."

FAIR-HF was sponsored by Vifor Pharma. Anker reports receiving lecture fees from Roche Pharma and Teva; fees from Vifor Pharma as a member of the FAIR-HF executive committee; and lecture and consulting fees from Vifor Pharma and Amgen. Disclosures for the coauthors are listed in the paper. Lewis reports receiving research grants from Novartis and Amgen and serving as a consultant to Amgen. Jessup has reported serving on an advisory board for Medtronic. Konstam reports having served as consultant to or received research grants from Merck.


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