European Heart Journal Advance Access originally published online on January 12, 2008
European Heart Journal 2008 29(4):566-567; doi:10.1093/eurheartj/ehm600
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Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regiments of darbepoetin alfa in patients with heart failure and anaemia: reply
University Medical Center Groningen Department of Cardiology
PO Box 30 001
9700 RB Groningen
The Netherlands
Tel: +31 50 3612355
Fax: +31 50 3614391
Email: d.j.van.veldhuisen{at}thorax.umcg.nl
Amgen Inc. Global Development
Thousand Oaks, CA
USA
Amgen Limited
Biostatistics Department
Cambridge
UK
We appreciate the comments by Drs Leszek and Kruszewski. It is clear that they recognize that the aetiology of anaemia in heart failure is complex and that the non-invasive assessment of body iron stores is challenging. Non-invasive determination of iron status typically includes ferritin and TSAT. Ferritin is an acute-phase reactant. Its level can change independently of iron status, which limits its use as a marker for body iron stores. As Leszek and Kruszewski noted, the coefficient of variation for basal ferritin in the placebo and darbepoetin alfa groups is 112 and 117%, respectively. This is in contrast to the coefficient of variation for basal TSAT in the placebo and darbepoetin alfa groups of 32 and 35%, respectively. Thus, in our study, subjects with Hb concentration between 9.0 and 12.5 g/dL and a TSAT 
15% were randomized to receive placebo or darbepoetin alfa.1 All subjects received 200 mg/day of oral elemental iron unless ferritin was >800 µg/L. During the study, the majority of subjects in each treatment group (>76%) received oral iron. Iron utilization in the three treatment groups was similar. There were no dose adjustments of iron and no use of intravenous iron.
Significant efforts were undertaken to identify the causes of the six deaths. The lack of relation between death and the treatment regimens was determined by the individual investigators at the subjects' sites; the authors reported the investigators' findings. Demographics, co-morbidities, concomitant medications, and laboratory parameters, including Hb and iron parameters, were closely scrutinized. Although iron toxicity is an interesting hypothesis, only three of the six subjects who died received oral iron for the duration of treatment (120–155 days). Two subjects who died in the weight-based dosing group did not receive oral iron. Additionally, the weight-based dosing subject who died 7 days after the first administration of darbepoetin alfa received iron for only 1 week. The aetiologies of death are most consistent with the natural history of heart failure. Patients with heart failure are ill2 and observational data suggest that the presence of anaemia in subjects with heart failure increases the risk of mortality and morbidity. The questions raised by Drs Leszek and Kruszewski highlight how important trials to identify new treatments for heart failure are. The currently enrolling RED-HF Trial3 will determine the impact of treatment of anaemia with darbepoetin alfa on morbidity and mortality in subjects with heart failure and will provide additional insights into the interplay of Hb, iron, and clinical outcomes in heart failure.
References
- Van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJA, Wasserman SM, Baker N, Rosser D, Cleland JGF, Ponikowski P. A randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anemia. Eur Heart J (2007) 28:2208–2216.
[Abstract/Free Full Text] - Okonko DO, Van Veldhuisen DJ, Poole-Wilson PA, Anker SD. Anaemia of chronic disease in chronic heart failure: the emerging evidence. Eur Heart J (2005) 26:2213–2214.
[Free Full Text] - Van Veldhuisen DJ, McMurray JJV. Are erythropoietic stimulating proteins safe and efficacious in heart failure? Why we need a large randomised outcome trial. Eur J Heart Fail (2007) 9:110–112.
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