Reply
Sir,We appreciate the comments by Dr Vaage-Nilsen on the section on Iron Management from the recently revised European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. In fact, they highlight two of the problems with the creation of clinical practice guidelines in general.
The first problem relates to what evidence to include and what to exclude in formulating such guidelines. Dr Vaage-Nilsen alleges that we omitted evidence in relation to this section, and also that some of the newer studies in relation to high and low molecular weight iron dextran were not considered. As the Methodology section from the revised EBPG indicates, a very comprehensive literature search involving over 5000 abstracts was initially conducted, and although much of this evidence did not end up being included in the Guidelines bibliography, this was only after a thorough assessment and scrutinisation of the quality of evidence available to support the various recommendations. Thus, some evidence was indeed omitted, but it is incorrect to assume that the evidence was not considered. The Working Group for the Guidelines was aware of the recent publications suggesting differences in the safety profile between the older high and the newer low molecular weight iron dextran complexes [1,2], and although these studies are of interest, the data were considered to be preliminary and not strong enough to justify a recommendation to use low molecular weight iron dextran at the present time. True anaphylactic reactions to intravenous iron compounds only occur with iron dextran due to pre-formed dextran antibodies; these antibodies do not cross-react with iron sucrose or iron gluconate, and no such antibodies have been detected against sucrose or gluconate. Thus, there is a physiological justification for having concern about severe life-threatening reactions to iron dextran, but not iron sucrose or iron gluconate. It may be (but is still not yet proven) that the incidence of these severe reactions is less with the lower rather than the high molecular weight dextran complex, but even with the low M.W. iron dextran they still occur. In the report by Fishbane et al. [3], 27 patients (4.7%) had adverse reactions that were related to the low molecular weight iron dextran. In addition, four of these patients (0.7%) had reactions that were classified as serious (one cardiac arrest; three hospitalisations). Ten patients (1.7%) had reactions that were classified as anaphylactoid.
Vaage-Nilsen also makes reference to the paper by Chertow et al. [4]. As he acknowledges, this paper was published in the same issue of this Journal as the Guidelines were published, and thus was not available to the EBPG Working Group. However, data reported in this paper suggest that reactions to even the low molecular weight iron dextran can be fatal (9 deaths reported by Chertow et al. [4]). Thirty one deaths due to iron dextran were also reported by Faich and Strobos [5]. In the paper by Chertow et al. [4], which Nebo generously supported, the authors analyse prescribing data, noting that ‘the rates for total adverse events are significantly lower among those patients receiving low molecular weight iron dextran compared to those on iron gluconate’. This conclusion contradicts other findings regarding the relative safety of these two products [5]. We feel that further studies are required, not only comparing low and high molecular weight iron dextran, but also iron sucrose and iron gluconate. In another report by Charytan et al. [6], 130 patients who were sensitive to either iron dextran or iron gluconate received intravenous iron sucrose therapy to correct iron deficiency. A history of intolerance to iron dextran alone was reported in 109 patients, to iron gluconate alone in 6 patients, and to both preparations in 15 patients. There were no serious adverse advents related to iron sucrose therapy in all 130 patients and the 14 non-serious events in 8 patients included diarrhoea, nausea, vomiting, dry mouth and skin irritation, none of which resulted in discontinuation of therapy. The Working Group acknowledges that there are no randomised controlled trials comparing the safety of the available intravenous iron preparations, but reviewing the evidence as a whole, it was generally accepted that the most favourable safety profile was associated with iron sucrose. This is mainly in relation to immediate reactions, but Vaage-Nilson quite rightly draws attention to the concerns regarding increased susceptibility to infection and oxidative stress. While there are many published in vitro and ex vivo studies on this issue which mandate against not being too liberal with intravenous iron, at the present time there is no evidence that this extrapolates into clinical harm for the patient. The papers by Zager et al. [7] and Agarwal et al. [8], both of which were published in 2004 (and were therefore not available by the time the Guidelines were formulated), are of interest, but again have a number of limitations. The effects seen are transient and reversible, and there is no evidence that they translate into long-term clinical harm. Again, further research in relation to this important topic is required.
In summary, we acknowledge the limitations of the available evidence in relation to comparisons of the different intravenous iron preparations. Nevertheless, we felt that we did our best with the available published data, and do not feel that we would change our recommendations either then or now. We do, however, acknowledge that there may be specific individual circumstances when intravenous iron dextran may be the appropriate therapy, despite our statement that this preparation is "not generally recommended".
Thus, even if we were to assume that the lower molecular weight iron dextran is safer than the older high M.W. compound, the fact that such reactions still occur was the basis of our comment that ‘iron dextran is not generally recommended’. It should, however, be noted that the revised EBPG do NOT state that the physician should NOT use intravenous iron dextran.
King's College Hospital Renal Unit London SE5 9RS UK Email: Iain.Macdougall{at}kingsch.nhs.uk
References
- Coyne DW, Adkinson NF, Nissenson AR, Fishbane S, Agarwal R, Eschbach JW, Michael B, Folkert V, Batlle D, Trout JR, Dahl N, Myirski P, Strobos J, Warnock DG. Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int 2003; 63: 217–224[CrossRef][Web of Science][Medline]
- Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis 2001; 37: 859–861[Medline]
- Fishbane S, Ungureanu V-D, Maesaka JK, Kaupke CJ, Lim V, Wish J. The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis 1996; 28: 529–534[Medline]
- Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant 2004; 19: 1571–1575
[Abstract/Free Full Text] - Faich G, Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans. Am J Kidney Dis 1999; 33: 464–470[Web of Science][Medline]
- Charytan C, Schwenk MH, Al-Saloum MM, Spinowitz BS. Safety of iron sucrose in hemodialysis patients intolerant to other parenteral iron products. Nephron Clin Pract 2004; 96: c63–c66[CrossRef][Medline]
- Zager RA, Johnson AC, Hanson SY. Parenteral iron nephrotoxicity: potential mechanisms and consequences. Kidney Int 2004; 66: 144–146[CrossRef][Web of Science][Medline]
- Agarwal R, Vasavada N, Sachs NG, Chase S. Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease. Kidney Int 2004; 65: 2279–2289[CrossRef][Web of Science][Medline]
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