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Anaemia Management
Erythropoiesis-stimulating Agents in Chronic Kidney
Disease – for Better or for Worse
a report by
Nathalie Thilly
1
and Luc Frimat
2
1. Associate Professor and Lecturer, Epidemiology and Public Health;
2. Professor of Nephrology, University Hospital of Nancy
Anaemia is a major complication of chronic kidney disease (CKD). cardiovascular disease), primary outcomes (morbidity, death, adverse
Developing early in the course of the disease, it affects nearly all end- events, quality of life, left ventricular function) and follow-up duration
stage renal disease patients.
1,2
Renal anaemia has been shown to be (24–135 months). Apart from the Besarab et al. study,
31
these were small
associated with impairment in quality of life,
3
cognitive decline,
4
and follow-up was short. The trials were then lacking the depth to show
decreased exercise capacity
5
and increased mortality.
6
a statistically significant result. Trends were differing and the nature of the
relationship between Hb level and mortality remained unclear.
Erythropoiesis-stimulating Agents – the Cornerstone of
Therapy for Renal Anaemia Two RCTs – Cardiovascular Risk reduction with Early Anaemia Treatment
The introduction of erythropoiesis-stimulating agents (ESAs) in 1989 by Epoetin beta (CREATE) and Correction of Haemoglobin and Outcomes
offered a new way to manage renal anaemia, both during maintenance in Renal insufficiency (CHOIR) – published at the end of 2006, raised
dialysis and in the pre-dialysis period. In the US, the number of again the controversy concerning the optimal target Hb level.
haemodialysis patients who were administered at least one blood Representing the largest studies in pre-dialysis patients published to date,
transfusion per quarter decreased from 16% in early 1989 to 3.3% in they tested the hypothesis that higher Hb would lead to improved patient
1992.
7
Moreover, mean haemoglobin (Hb) level in US patients on dialysis outcomes. The CREATE study
34
enrolled 603 stage three and four CKD
increased from 9g/dl in 1989 to 11.7g/dl in 2002.
8
Numerous benefits patients, randomly assigned to a target Hb value in the normal range
have been associated with good anaemia control in CKD, mainly in (13–15g/d) or the subnormal range (10.5–11.5g/dl). Epoetin beta was
observational studies, including lower all-cause mortality and reduced initiated at randomisation in the first group or only after the Hb level fell
occurrence of cardiovascular complications and mortality.
8–12
below 10.5g/dl in the second group. The results showed no difference
between the groups with regard to the primary end-point, which was a
Since 1997, the US National Kidney Foundation and the European Dialysis composite of eight cardiovascular events. The left ventricular mass index
and Transplant Association have published and updated clinical practice remained stable in all patients and the mean decline in glomerular
guidelines describing how to diagnose and treat anaemia both before filtration rate (GFR) over the three-year follow-up period did not differ
and after dialysis.
13–17
Despite guidelines recommending the initiation of between groups. The CREATE study was probably lacking the depth to
ESA therapy whenever the Hb level was lower than 11g/dl, detailed demonstrate any difference between the two groups; indeed, the annual
inquiries both pre-dialysis
18–22
and during maintenance dialysis
23–26
event rate used to calculate the sample size was actually much lower than
showed that ESAs were not being prescribed to all CKD patients who expected (6% versus 15%). The CHOIR study
35
enrolled 1,432 patients
required them. However, an improvement in renal anaemia care has been having an estimated GFR of 15–50ml/min/1.73m
2
in 130 centres. Patients
recorded over the last decade, showing a greater use of ESA therapy were randomly chosen to receive a dose of epoetin alfa targeted to
resulting in higher mean Hb levels.
18,20,27
This consistent improvement in
therapeutic care may be attributed to the successful implementation of
guidelines and a growing body of literature showing benefits of the ESA
Nathalie Thilly is an Associate Professor and Lecturer in
Epidemiology and Public Health in the Department of Clinical
therapy, although no causal relationship should be assumed.
Epidemiology and Evaluation of the University Hospital of
Nancy. Since 2004, her research interests have been focused
The Controversies Associated with the Haemoglobin
mainly on epidemiology and therapeutic evaluation in the
field of kidney diseases. Professor Thilly has taken an active
Target Level
part in clinical research programmes in collaboration with the
Notwithstanding the widely accepted benefits of proper management of
nephrology department and has published on the topic
several articles and presented internationally.
renal anaemia, debate has raged recently about optimum Hb target
levels. Should we aim at complete correction of anaemia compared with
E:
n.thilly@chu-nancy.fr
partial correction? Can we say “the higher the Hb concentration, the
Luc Frimat is Professor of Nephrology at the Nancy
better the clinical benefits of the ESA therapy”? Is there a threshold we
University of Medicine. He spent a year working on the
CHOICE study at the Welch Center for Prevention,
must not exceed at the risk of reversing the benefits? Is this threshold the
Epidemiology, and Clinical Research at Johns Hopkins
same whatever the stage of CKD and the patients’ co-morbidities? University, Baltimore. Professor Frimat is the co-ordinator of
the regional network of renal cares, named Nephrolor, and
Head of the Commission of Epidemiology of the Société de
Before 2003, according to the literature review of Volkova and Arab,
28
Néphrologie. He is involved in the regional and national
only five well-conducted randomised control trials (RCTs) had focused on
end-stage renal disease registry and in many cohort studies.
He has a PhD in epidemiology.
investigating the association of Hb levels with patient outcomes.
29–33
These
trials were heterogeneous in terms of study population (with or without
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