Department of Renal Medicine, St James's University Hospital, Beckett Street, Leeds, UK
Sir,
The recently declared European Best Practice Guidelines for Renal Anaemia [1] represent an advance on the US National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) equivalent [2] in at least one respect. They indicate the distribution of outcome values likely to be required in order to give satisfactory compliance with guidance, as demonstrated in the UK Renal Registry Report 1998 for renal failure populations [3]. Target guideline 5A, in particular, suggests that a mean/median haemoglobin (Hb) of 1212.5 g/dl is to be expected if 85% of values fall above the recommended `target minimum' of 11 g/dl. The basis of these estimates is not given and more realistic values may be derived from basic statistical principles applied to recent registry data. The distribution of Hb outcome values in dialysis populations is normal, or near normal, in data from The European Survey on Anaemia Management (ESAM) and the UK Renal Registry [3]. Any Gaussian curve can be described in units of standard deviation (SD) (z score) [4]. Since the first SD from any mean defines 34% of the population under review, and since 50% will be above the mean, a value at 1 SD below the mean separates 84% above (34+50) and 16% below it. In fact, a value 1.035 SD below the mean defines 85% above and 15% below (z score=-1.035) [4]. The predicted mean of any normally-distributed population having 85% above a declared minimum is then given by (minimum+[1.035xSD]) (Figure 1).
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There is no reason to suppose that renal units of any size will differ from the UK experience. It is entirely possible that in the future there will be a systematic narrowing of range in Hb outcome distributions, but no formal methods are available yet for that to be achieved. The uraemic marrow, charged up with iron and erythropoietin, has a momentum that cannot be simply switched off, unlike say Kt/V, and the opportunity costs, at least, of intense patient monitoring will be very great. It appears that the European Guidelines, because of centre variation and the intractability of outcome ranges, may lead to clinical risk, for example of thrombosis, at Hb values over 14 g/dl [6,7].
Most current guidelines tend to be strong on efficacy but, as yet, limited in regard to evidence of effectiveness and efficiency [8]. It was the Domino's Pizza Company in the US who found that their ideal delivery time of <30 min was not achievable without injury to a member of the public and great cost to themselves in the courts. A declaration of ideal outcomes that does not carry evidence of practicality and safety is likely to be vulnerable to similar mishap, so that it is important to have an accurate estimate of outcome distributions in advance.
Since nephrologists are rehearsing the principles of evidence-based clinical intervention ahead of most medical specialities we have a unique responsibility to get them right.
References
Chairman, Working Party on the Management of Anaemia in Chronic Renal Failure, 19971999, Melmerby, Cumbria, UK
Sir,
On behalf of the Working Party on the Anaemia of Chronic Renal Failure of the ERA, I would like to thank Dr Will for his comments. The object of the guideline exercise is dialogue and new studies, which we hope will result in improved and more appropriate guidelines. The ERA plan to launch a revised version of the anaemia guidelines in 2001 at the meeting in Vienna, at which time the results of the second European Study of Anaemia Management (ESAM) will be available, and we shall see whether the first exercise has made any impact on European practice in this area, and if so, what.
All, including Dr Will, will have noticed that the commentary on the target haemoglobin in guideline 5 is unusually long and detailed. Even so it was shortened considerably before publication, and in this abbreviation, reference to the statements about the likely mean haemoglobin concentration if the target of 85% of the population over 11 g/dl is attained, were omitted, for which we apologize.
This basis was (i) data from the 1998 report of the UK Renal Registry (the 1999 report cited by Dr Will as `in press' was not, of course, available to us) and (ii) unpublished detailed serial population data on haemoglobin concentrations from the AMGEN study [1], kindly provided by Dr David Goodkin their Figure 8.4 indicates a difference of between 1 and 1.5 g/dl between the mean haemoglobin and 10 g/dl, if 85% of the population attained that level. An important additional point was that this difference was constant at all lower haemoglobin concentrations. This conclusion was supported by the unpublished data from the AMGEN study, which showed no narrowing in distribution with increasing haemoglobin, and a difference of 1.46 g/dl between observed mean haemoglobin and the point above which 85% of the population fell. Again, in these serial data the figure was independent of the absolute concentration of haemoglobin, that is the distribution remained Gaussian and the SD did not narrow with increasing haemoglobin concentration. We therefore chose to use `11.5 g/dl higher' until more data accumulate. We were aware this implied setting a minimum target of between -0.5 and -1 SD below the mean for the population under study.
Also, we did not have space in the guidelines to comment on the make-up of the group of patients who fall short of the target concentration. These consist of (i) a `long-term' population whose haemoglobin concentrations remain persistently low: patients with haemoglobinopathies, myeloma, malignant disease and persistent inflammatory states; and (ii) a larger `transient' population of patients (the majority) who either have just suffered a fall in haemoglobin concentration, usually for identifiable and correctable reasons, or have presented late and are in the early stages of dialysis. Analysis of data from three British units suggests that if one takes a cross-section of the whole population in a dialysis unit, then it is very difficult to meet the 85% figure, and a figure of 80% may prove more realistic. An alternative is to add that the attainment in relation to the target should be examined for a population who have been on dialysis for at least 6 months, perhaps longer. Again we need more data.
Dr Will is concerned that our guidelines `may lead to clinical risk at the upper end of the Hb range' citing the paper of Besarab et al. [1] in which patients on dialysis with cardiovascular disease were studied. This is an important caveat. Our conclusion, from a careful study of all the available evidence, was in contrast; that `To date, no evidence of deleterious effects of normalising the haemoglobin concentration in the majority of uraemic patients has emerged' [guidelines, p. 12]. Even in those with cardiovascular disease, only the AMGEN study [1] has pointed to any increased risk. However, their data on access thrombosis are so at variance with European experience, as outlined in the ESAM data and elsewhere, that we feel they can be ignored. Also, we noted that in the AMGEN study `there were no statistically significant differences between the normal haematocrit and the low haematocrit group either in the number of cardiovascular deaths (125 vs 112) or the incidence of angina, coronary interventions, congestive heart failure or myocardial infarction over a period of 30 months (mean 14) until the premature termination of the trial' [guidelines p. 13]. The trial was terminated early because of an increased number of deaths in the normal haematocrit group (183 vs 150, RR 1.3, CI 0.91.9, P>0.05) from causes other than cardiovascular disease. There are additional data, including one prospective (but uncontrolled) study [2] to suggest that mortality is actually lower with higher haemoglobin concentrations.
Therefore, the fact that our recommendations imply that 15% of patients will have a pre-dialysis haemoglobin concentration of >14 g/dl does not perturb us, even though we cautioned that in such patients post-dialysis haemoglobin concentration must be measured to assess the temporary effects of ultrafiltration.
Undoubtedly in the 2001 guidelines, guideline 5 on target haemoglobin will undergo modification. Even if it proves safe, whether the attainment of an increment in pre-dialysis haemoglobin concentrations above 1011 g/dl is a useful and worthwhile way to target scarce health resources will require further careful studies.
References