ACCEL | High-end treatments for anemia have failed, but earlier and simpler Rx may be better

Iron deficiency is one of the most common nutritional deficiencies worldwide, affecting one-third of the general population. Several chronic disorders may be complicated by iron deficiency but only recently has it been reported to be a frequent comorbidity in stable heart failure (HF) patients, regardless of ejection fraction, as well as in individuals hospitalized with worsening HF. According to clinical trial data, the range of anemia reported in patients with HF has ranged from 10% to 26%; in HF registries, the anemia rate has been even higher: 15% to 55%.

In people with HF, iron deficiency has been associated with impaired functional capacity, poor QOL, and increased mortality, irrespective of the presence of anemia. CONFIRM-HF (Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure) was a double-blind trial that enrolled 304 stable, symptomatic HF patients from across nine European countries.¹ Patients were randomized 1:1 to treatment with intravenous (IV) iron (n = 152) or placebo (saline, n = 152) for 52 weeks.

Weekly dosing with IV iron resulted in a significant increase from baseline in 6-minute walk test distance at 24 weeks (the primary endpoint), increasing distance walked from 33 to 42 meters or roughly an additional 108 to 138 feet added to baseline distance. Conversely, patients who received placebo (saline) showed a similar-sized change from baseline but in the opposite direction with a reduction rather than an increase in their 6-minute walking test distance (for a total difference between the two groups of 33 ± 11 meters; p = 0.002). At 52 weeks, there was concomitant improvement in other measures of functional status and QOL among those treated with IV iron compared to placebo.

The investigators also noted a significant decrease in the risk of hospitalization due to worsening HF with active therapy (HR: 0.39; p = 0.009) and, in post-hoc analysis, a similar beneficial effect was seen for the risk of recurrent hospitalizations for worsening HF (HR: 0.30; p = 0.0019). Throughout the study, an improvement in NYHA class, Patient Global Assessment scores, QOL, and fatigue score was seen in patients treated with iron supplementation and all achieved statistical significance from week 24 onwards.

Interestingly, previous work by Ponikowski and colleagues has suggested that iron deficiency, but not anemia, is associated with reduced exercise capacity in HF patients² and poor outcome.³ According to the ESC.14 presenter of the CONFIRM-HF results, Piotr Ponikowski, MD, Medical University, Centre for Heart Disease, Wroclaw, Poland, "In clinical practice, we don't bother at all about iron deficiency because this is a very poorly recognized comorbidity, though it affects half of the population regardless of their hemoglobin level. This trial shows that iron deficiency is an important comorbidity that we can detect using biomarkers – and once we detect it, we can treat it and improve exercise tolerance."

Also at ESC.14, Josep Comin-Colet, MD, Hospital del Mar Heart Failure Program, Barcelona, Spain, reported the results of an analysis of 449 iron-deficient chronic HF patients randomly assigned to receive IV ferric carboxymaltose or placebo for 24 weeks. They measured chronic heart failure symptoms, QOL, and exercise capacity at the start of the study, and after 4, 12 and 24 weeks. They found:

• Chronic heart failure symptoms, quality of life, and exercise capacity improved with the intravenous iron treatment.
• After just 4 weeks, patients receiving IV ferric carboxymaltose had a significantly improved QOL compared to those who received placebo.
• The beneficial effects of IV ferric carboxymaltose on QOL were also seen at the later time points (12 and 24 weeks).
• Improvements were not influenced by patients' anemia status.

GUIDELINES STATUS

The 2012 European Society of Cardiology guidelines, for the first time, mention iron deficiency as a comorbidity in HF. The guidelines state that treatment with carboxymaltose may be considered to improve symptoms, exercise capacity, and QOL in patients with HF and a ferritin level < 100 mcg/L or between 100 and 299 mcg/L, if transferrin saturation is < 20%.

The current American College of Cardiology/American Heart Association (ACC/AHA) HF guidelines⁴ note that two trials have raised concerns that patients treated with an erythropoiesis-stimulating agent may have an increased risk of cardiovascular events. Moreover, in RED-HF (Reduction of Events With Darbepoetin alfa in Heart Failure), treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic HF and mild-to-moderate anemia.

However, the 2013 ACC/AHA guidelines note that a trial using IV iron as a supplement in patients with HF and reduced ejection fraction and iron deficiency (FAIR-HF) showed an improvement in functional status compared to control (saline) and no untoward adverse effects of active therapy.⁵ The ACC/AHA guidelines note that "in the absence of a definitive evidence base, the writing committee has deferred a specific treatment recommendation regarding anemia."

Take-aways

• Iron deficiency is a frequent comorbidity in patients with stable HF or admitted to the hospital for worsening HF.
• HF complicated with iron deficiency is associated with impaired functional capacity, poor QOL, and increased mortality.
• Treatment of symptomatic, iron-deficient HF patients resulted in sustainable improvement in functional capacity, symptoms, and QOL and may a lower risk of hospitalization for worsening HF.

References

1. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Eur Heart J. 2014 Aug 31. [Epub ahead of print]
2. Jankowska EA, Rozentryt P, Witkowska A, et al. J Card Fail. 2011;17:899-906.
3. Klip IT, Comin-Colet J, Voors AA, et al. Am Heart J. 2013;165:575-82.
4. Yancy CW, Jessup M, Bozkurt B, et al. J Am Coll Cardiol. 2013;62:e147-e239.
5. Anker SD, Comin C J, Filippatos G, et al. N Engl J Med. 2009;361:2436-48.

Keywords: ACC Publications, CardioSource WorldNews

< Back to Listings