Evidence-based Guidelines provide a valuable framework for developing and implementing treatment strategies for patients. As such they should be based on a comprehensive search and appraisal of prevailing evidence. We write to express concerns regarding the omission of evidence relative to the above mentioned section.
The Guidelines recommend the use of iron sucrose and iron gluconate over iron dextran. The bibliography indicates that newer studies documenting the differences in regard to safety between high and low M.W. iron dextran were not considered. Neither did the drafting of the Guidelines include recent documentation concerning the acute toxicological profiles of the available parenteral iron formulations or issues associated with long term safety.
In the Guidelines there is an assumption that iron dextran preparations can be considered as a single class of product and as such the recommendations are dismissive of all iron dextran formulations. Closer scrutiny of recent published literature would reveal that low molecular weight iron dextran offers a safety profile that is very different from the older high molecular weight iron dextran complexes [16]. Low M.W. iron dextran has a significantly lower risk of both serious and non-serious acute adverse drug events compared to high M.W. iron dextran [16].
In the same issue of Nephrology Dialysis Transplantation, in which the Guidelines were published, Chertow et al. evaluates all reported adverse drug events recorded by the FDA during three years (19982000), where a total of 21 million doses of 100 mg iron were administered. The study reports a superior safety profile for low molecular weight iron dextran (INFeD®/CosmoFer®) vs the high molecular weight iron dextran (Dexferrum®). The study also reveals that the rates for total ADEs are significantly lower among those patients receiving low molecular weight iron dextran than those receiving iron gluconate.
Studies that specifically address serious or life-threatening adverse events suggest that they are rare in patients administered low molecular weight iron dextran [1,3]. The largest prospective studies on the safety of parenteral iron are not comparative, so it is unclear as to whether these rare serious ADEs are less common with one particular parenteral iron than with other forms of intravenous iron. We suggest that the paucity of evidence (especially comparative) makes it inappropriate to indicate which may be the safest IV iron preparation.
Traditionally a safety analysis of pharmaceutical products considers both the short and long term safety aspects covering typically acute adverse drug events and the potential long term consequence of the toxicological profile. We suggest that in preparing the next revision of the European Guidelines a comprehensive analysis should be conducted in regard to the difference between the toxicological profiles of the currently available parenteral iron formulations. We draw your attention to recent studies that focus on long term safety concerns associated with the loosely bound iron complexes, iron sucrose and iron gluconate. These studies relate to free/labile iron and oxidative stress and cytotoxicity which are considered clinically important and therefore influence the choice of parenteral iron.
Zager et al. (2004) [7]:
"Parenteral iron formulations have potent, but highly variable, cytotoxic potentials which appear to parallel degrees of cell iron uptake:(iron sucrose>iron gluconate << low M.W. iron dextran)"
Agarwal et al. (2004) [8]:
"The data in humans confirm the suggestion of Zager et al. that there was direct renal injury with injected iron sucrose."
The European Best Practice Guidelines should also consider that low M.W. iron dextran administered as total dose infusion (TDI) is the only real treatment option for iron deficient predialysis patients, home hemodialysis, or PD patients, since weekly visits may be unrealistic. This is also the recommendation in the K-DOQI guidelines.
In conclusion, we request that the evidence relating to both the short and the long term safety profile of currently available parenteral iron compounds is appraised and considered in a revision of the European Best Practice Guidelines and the K-DOQI Guidelines. We especially urge the appointed guideline committee to acknowledge and review the safety literature regarding low M.W. iron dextran (CosmoFer®/INFeD®), which will ensure that they have embraced all current parenteral iron supplement options, and add credibility and support to such a publication.
Conflict of interest statement. None declared.
Nebo a/s President Roervangsvej 30 DK 4300 Holbaek Denmark Email: rie.greve{at}pharmacosmos.com
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