European Heart Journal Advance Access originally published online on January 12, 2008
European Heart Journal 2008 29(4):565-566; doi:10.1093/eurheartj/ehm598
Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia
Institute of Cardiology
Heart Failure and Transplantology Department
04-628 Warsaw Alpejska 42
Poland
Tel: +48 22 34 34 484
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Email: przemyslaw.leszek{at}ikard.pl
Institute of Nuclear Chemistry and Technology
Department of Radiobiology and Health
Protection
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PolandTel: +48 22 811-07-36Fax: +48 22 811-15-32Email: marcinkr{at}ichtj.waw.pl
We read with great interest the article by van Veldhuisen et al.,1 who presented the results of randomized, double-blind, placebo-controlled study in anaemic patients with heart failure (HF), in whom anaemia was corrected with subcutaneous darbepoetin alfa and oral iron administration. Although several relatively small studies have shown that anaemia correction might be beneficial in HF patients, that large scale, multicentre trial revealed a much less favourable outcome.
Yet, although the authors made every effort to select the study population accurately and achieved great precision assessing anaemia aetiology and iron homeostasis, there are still several issues to be discussed. The high coefficient of variability (117%) of the basal ferritin level, a traditionally preferred clinical marker for body iron stores, as well as other markers of iron metabolism, suggests a significant diversification within the study group with regard to iron homeostasis. Keeping in mind the complexity of aetiology of anaemia in HF patients, it is not clear whether authors fully differentiate between true iron deficiency, and anaemia of chronic disease. Although both types are characterized by decreased erythropoesis, they vary in iron availability, this fact seems important, as the oral iron supplementation was guided by ferritin level in that study.2
As darbepoetin alfa supplementation enhances iron utilization for haeme synthesis, patients receiving darbepoetin alfa probably got more iron than placebo treated group. Indeed, a slight, but insignificant increase in ferritin, plasma iron, and TSAT in comparison to baseline was reported in body-weighted dose group of patients. Of note is the fact that five out of the total of six deaths occurred in the latter group.
Moreover, plasma contains also non-transferrin bound iron (NTBI)—not assessed in the present paper—which might contain a potentially toxic form of iron that could exert a harmful effect related to the increase of toxic cellular labile iron pool (LIP). The oxidative stress associated with inflammatory conditions frequently observed in HF accompanied by increase in NTBI may lead to an increase in the LIP (via both transferrin dependent and independent pathways) and formation of highly reactive oxygen species,3 causing an increased myocyte loss, alteration of myocyte function by affecting several excitation–contraction coupling proteins, and also interstitial fibrosis.4 Although the authors claimed six death incidents unrelated to the treatment regimen, they failed to demonstrate the cause of the fatal outcome. This vagueness might be at least partially cleared out if we could see an additional analysis which would incorporate an adjustment of factors involved in iron homeostasis, which might possibly account for the potential causes of the fatal outcome. It would also be welcome if the authors might provide the absolute amount of iron received by the patients studied to eliminate the association of deaths with the putative iron toxicity.
References
- van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJ, Wasserman SM, Baker N, Rosser D, Cleland JG, Ponikowski P. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J (2007) 28:2208–2216.
[Abstract/Free Full Text] - Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med (2005) 352:1011–1023.
[Free Full Text] - Kruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res (2003) 531:81–92.[Web of Science][Medline]
- Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (2006) 84:349–364.[CrossRef][Web of Science][Medline]
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