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Anaemia Management
Haemoglobin in Chronic Kidney Disease Patients – The Goalposts
May Move, but We Are Still on Target
a report by
Fernando Carrera
Senior Consultant Nephrologist, Eurodial, Leiria, Portugal
While it is relatively common for a medical article to quote Hippocrates, body of scientific work seems to show that the normalisation of
this one instead takes its structure from Hegel and Hegelian dialectic, in haemoglobin in CKD patients, which was justified by earlier studies that
which a thesis is put forward for consideration in order to provoke a are now deemed observational and/or coincidental, does not confer
reaction or contradictory antithesis, with this tension being reconciled by cardiovascular-related advantages on this population. Further, it is claimed
the formulation of a synthesis. that a normalisation or total correction may actually cause grave harm in the
form of myocardial infarction, stroke, hospitalisation and even death from
Let us apply this framework to a concrete situation – that of correcting heart failure – all the things a higher haematocrit was supposed to prevent,
anaemia in chronic kidney disease (CKD) patients. Almost all patients in as can be seen in larger observational studies such as the Dialysis Outcomes
the advanced stages of CKD have anaemia, which is mainly caused by the and Practice Patterns Study (DOPPS); and so is postulated our counterthesis.
undersynthesis of endogenous erythropoietin. The availability of
recombinant human erythropoietin from the late 1980s has meant that Strong words – almost fighting words – have been used to shoot down
for approximately 20 years it has been possible to correct or normalise the prior beliefs, starting with the title of Strippoli’s The Lancet article:
haemoglobin levels of CKD patients. These drugs have made red blood ‘Haemoglobin targets: we were wrong, time to move on’. His editorial
cell transfusions redundant, thus avoiding their concomitant risks and describes the “meta-analysis which brings an expected end to a
impacting favourably on the quality of life of patients. somewhat artificially delayed story [of normalisation/optimisation/total
correction]”. He claims no further trials into target haemoglobin
Why did this ‘normalised’ thesis prevail, and for so long? Anaemia has long concentrations are required “because of … the credibility of the scientific
been cited as a leading cause of heart failure, and reduced haemoglobin has community, after such a long history of contradictions’.
15
been shown by many researchers to decrease muscle strength, exercise
capacity, cognitive ability and libido while increasing morbidity and The ‘scientific community’, however, did not and does not rest. Several
mortality;
1,2
in short, it leads to a worsened quality of life and has high direct members of said community have addressed what they see as the flaws
and indirect costs for both healthcare and society. Higher haemoglobin in this series of studies and the doubts still remaining in their wake.
16,17
levels improve oxygen–tissue transport, impacting positively on tissue The former include the methodology, design, population and conduct of
hypoxia and oxidative stress – i.e. reducing inflammation and retarding the the studies; the latter, the validity of the findings and the degree to which
progression to end-stage renal disease. In sum, correcting or normalising the findings can be extrapolated to routine clinical practice.
haemoglobin levels has resulted in documented improvements in all the
above-mentioned areas,
3–6
the most significant of which is quality of life.
7
Let us now proceed to an examination of the counter- or contradictory
thesis. For the Besarab trial, “Patients at highest cardiovascular risk were
To return to Hegel, administering erythropoiesis-stimulating agents (ESAs) to chosen, to increase the likelihood that a beneficial event would be
target physiologically normalised haemoglobin levels in the CKD patient found…”.
15
This means that patients selected to be part of the study
population is the thesis; in this case, the thesis is a long-standing one, population were already in the high cardiac risk category, with congestive
although one that has not been without its detractors. Evidence-based heart failure or ischaemic heart disease. This is its most serious flaw.
medicine encourages government agencies and healthcare providers to
analyse this thesis and the costs of prescribing ESAs for CKD patients. The Levin,
16
Carrera and Macdougall
17
– as well as many others – raise several
financial load in question – US$10 billion in global sales in 2006
8
– is issues with respect to the CREATE and CHOIR trials. CREATE randomised
undoubtedly a major factor in the debate on the ‘ideal’ or ‘correct’ haemo- patients to either a higher group of haemoglobin 13.0–15.0g/dl or a lower
globin targets physicians should aim for in CKD patients. The deliberation on group of haemoglobin 10.5–11.5g/dl; CHOIR randomised patients to either
total normalised haemoglobin 13.0–15.0g/dl versus partial/incomplete or haemoglobin 13.5g/dl or haemoglobin 11.3g/dl. Both are open-label,
subnormalised haemoglobin 10.5–11.5g/dl, which has always been which can add distorting bias to the conduct of the trials in that healthier
simmering in the background,
9,10
has once again reached boiling point. patients are enrolled to obviate concerns over cardiovascular disease. The
CHOIR study enrolled 1,432 patients, seeking to determine the impact of
The 1998 Besarab trial results
11
and the summations of Parfrey and degree of anaemia correction on mortality and cardiovascular morbidity
colleagues in 2005
10
have been recently joined by the findings of the 2006 in CKD patients. It saw a high drop-out rate of 38%, with no explanation
Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin Beta given for 50% of these, and the analysis did not include all the
(CREATE) study,
12
those of the Correction of Haemoglobin and Outcomes in randomised patients, omitting those who had no event at trial end. In
Renal Insufficiency (CHOIR) study,
13
Phromminkiul et al.’s 2007 meta- terms of findings, could the statistically significant differences between
analysis in The Lancet
14
and its companion piece, Strippoli’s editorial.
15
This the two treatment groups – i.e. the greater baseline incidences of
© TOUCH BRIEFINGS 2007 13
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