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221Maedica A Journal of Clinical Medicine, Volume 5 No.3
2010
Anemia and iron deficiency New therapeutic targets in heart
failure?Gabriela BICESCU MD, PhD
Cardiology Department, Emergency University Hospital, Bucharest,
Romania
Anemia has been associated witholder age, diabetes mellitus,
chron-ic renal dysfunction, more advancedheart failure symptoms,
lower peakexercise capacity, and worse health-
related quality-of-life metrics. Anemia has also
been shown to be a powerful predictor of re-hospitalization
rates and survival in chronicheart failure.
Anemia ranges in prevalence from below10% among patients with
mild heart failuresymptoms to over 40% for patients with ad-vanced
disease. Its prevalence is similar amongpatients who have systolic
dysfunction andamong patients who have heart failure withpreserved
systolic function.
A complex interaction between impairedcardiac performance,
activation of neurohor-monal and inflammatory responses, renal
dys-function, drug effects, and bone marrow hypo-responsiveness
appears to contribute to thedevelopment of anemia. In a minority of
cases,the cause of anemia may be dilutional ratherthan a true
decrease in red-cell mass.
Iron deficiency prevalence is 5 to 21% andis often present in
association with heart failureand may curtail the absorption of
dietary iron.Gastrointestinal malabsorption, long-term aspi-rin
use, and uremic gastritis may also precipi-
tate iron-deficiency anemia. Chronic iron defi-ciency may, by
itself, reduce exercise capacity
and cause ultrastructural alterations in cardio-myocytes. It has
therefore been postulated thatiron supplementation may be
beneficial in pa-tients who have iron deficiency and heart fail-ure
regardless of whether anemia is present. Itseems logical to
consider whether correcting
anemia may improve functional capacity andsurvival. Iron is
essential not only for erythro-poiesis but also for several
bioenergetic pro-cesses in skeletal muscle.
Two small, placebo-controlled trials of intra-venous iron
therapy in patients with heart failurehave been reported
previously. In the first, 40patients with anemia received treatment
withintravenous iron or saline infusion for 5 weeks.There was a
significant improvement in the Min-nesota Living with Heart Failure
score, decreasedlevels of C-reactive protein and N-terminalprobrain
natriuretic peptide, and an increasedleft ventricular ejection
fraction and distanceon the 6-minute walk test.
In the FERRIC-HF (Ferric Iron Sucrose inHeart Failure) trial, 35
patients with iron defi-ciency received intravenous iron, aimed at
im-proving the ferritin level, or saline infusion.
In-travenous-iron loading decreased the New YorkHeart Association
(NYHA) functional class andimproved the patients global
assessmentscore.
The FAIR-HF (Ferinject Assessment in Pa-tients with Iron
Deficiency and Chronic Heart
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A Journal of Clinical Medicine, Volume 5 No.3 2010
Failure) trial enrolled 459 patients with NYHAfunctional class
II or III symptoms, a depressedleft ventricular ejection fraction,
and docu-mented iron deficiency. Patients were assignedto receive
200 mg of intravenous iron or in-fused saline weekly until their
iron stores werereplete. Then, intravenous iron or placebo
in-fusions were continued every 4 weeks up toweek 24. The primary
end points were the self-reported Patient Global Assessment and
theNYHA functional class at week 24. Secondaryend points included
the distance on the 6-min-ute walk test and health-related
quality-of-lifevalidated surveys at weeks 4, 12, and 24.
The degree of improvement in both endpoints was similar in
patients with anemia andthose without anemia. Furthermore,
significant
improvement in the secondary end points, in-cluding an increase
of more than 30 m in the6-minute walk distance, was also
observed.There was also a nonsignificant trend towardfewer
hospitalizations for cardiovascular rea-sons (hazard ratio, 0.53;
95% confidence inter-val, 0.25 to 1.09; P=0.08). Like any
well-doneclinical trial, this study has several limitations:the
dropout rate was higher than might be ex-pected for a relatively
short-term trial, the trials
primary end points, particularly the NYHAclass, were relatively
subjective and less con-vincing than physiological variables such
assubmaximal or maximal exercise capacity andthe number of patients
with mild symptoms(NYHA class II) was too small to show a
statisti-cal benefit.
Why patients with anemia did not have agreater symptomatic
benefit than patients with-out anemia also remains puzzling.
Whethercorrection of iron deficiency can favorably im-prove the
long-term release of biomarkers andproinflammatory cytokines,
improve ventricu-lar remodeling, decrease hospitalizations forheart
failure, and improve survival will requireadditional study.
In conclusion, this trial suggests a new ave-
nue for therapeutic exploration. Improvementin the quality of
life is increasingly important topatients with heart failure, and
the approachtaken in this study may have merit in patientswith
moderately symptomatic heart failure anddocumented iron deficiency.
Additional con-trolled trials will help to clarify the optimalroute
and duration of iron replacement, andprovide insight into possible
mechanisms of thebenefit.
Comment on a paper:G William Dec Anemia and Iron Deficiency. New
Therapeutic Targets in Heart Failure? N Engl J Med2009;
361:2475-2477
