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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2007 22(3):784-793; doi:10.1093/ndt/gfl483
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Is early treatment of anaemia with epoetin-{alpha} beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial

Iain C. Macdougall1, R. Mark Temple2, Jonathan T. C. Kwan3 on behalf of the EPO-GBR-2 Study Group

1The Renal Unit, King's College Hospital, Denmark Hill, London SE5 9RS, 2Heartlands Hospital, Renal Unit, Bordesley Green, Birmingham B9 5SS and 3SW Thames Renal & Transplant Unit, St Helier Hospital, Carlshalton, Surrey SM5 1AA, UK

Correspondence and offprint requests to: Dr Iain C. Macdougall, Consultant Nephrologist, The Renal Unit, King's College Hospital, Denmark Hill, London SE5 9RS, UK. Email: Iain.Macdougall{at}kingsch.nhs.uk



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
 References
 
Background. This multicentre, open-label prospective, randomized, comparative-group study evaluated the effects of maintaining haemoglobin (Hb) in pre-dialysis chronic kidney disease (CKD) patients.

Methods. A total of 197 patients were randomized to start subcutaneous epoetin-{alpha} (SC-EPO; EPREX®; 1000 U twice weekly) at an early stage of anaemia to maintain Hb at 11.0 ± 1.0 g/dl (group A, n = 65), or to allow Hb to fall to ≤9.0 g/dl before starting SC-EPO (group B, n = 132) (2000 U three times weekly); and subsequently maintaining Hb at 11.0 ± 1.0 g/dl.

Results. Of 132 patients randomized to group B, 55 progressed to treatment (-trigger). The study was prematurely terminated due to contraindication of the subcutaneous administration route. Mean weekly EPO doses at 1 year were 1471 U for group A; 820 U for group B; final doses were 2281 U for group A; 2099 U for group B. There was no significant difference between groups A and B with regard to left ventricular mass (–12.5 vs –9.7%; P = 0.82). In groups A and B, 48% and 52%, respectively, terminated the study because of dialysis/death, after a median of 36.3 and 27.3 months, respectively.

Conclusion. Early intervention to correct anaemia in CKD patients did not have a significant impact on LVM, the primary efficacy variable. Time to dialysis/death was not significantly different between groups A and B.

Keywords: anaemia; chronic kidney disease; early treatment; epoetin-{alpha}; pre-dialysis



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
 References
 
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD), and CVD mortality rates are 20–40-fold higher in patients with end-stage renal disease (ESRD) than in the general population [1]. Anaemia usually develops in patients with CKD because less erythropoietin is produced by diseased kidneys than by those that are healthy [2]. Anaemia is closely associated with the development of cardiac damage, which occurs during attempts to maintain adequate tissue oxygenation, and there is increasing evidence that even mild degrees of renal impairment may increase the risk of cardiovascular death [3]. Moreover, decreased haemoglobin (Hb) concentration has been shown to be an independent predictor of left ventricular hypertrophy (LVH) in patients with CKD [4] and of mortality in patients with heart disease [5].

The anaemia associated with CKD readily responds to treatment with recombinant human erythropoietin (epoetin, r-HuEPO), which is the standard treatment for anaemia in this patient group, and there is evidence to suggest that cardiac abnormalities in CKD patients can be reduced or prevented by early management of anaemia with epoetin therapy [6–8]. Correction of anaemia in pre-dialysis patients has also been associated with significant improvements in health-related quality of life, including overall well-being, energy levels, work and aerobic capacity, and cognitive, sexual and immune functions [9]. Furthermore, some studies have shown that normalizing Hb levels in dialysis patients improves quality of life [10–11], and may prevent the development of LV dilatation [10], although it does not fully reverse LV hypertrophy or dilatation [10] or exercise capacity [12].

Recently, a study of early and late intervention with epoetin-{alpha} on left ventricular mass (LVM) in patients with CKD reported that maintenance of Hb above 12 g/dl had similar effects to Hb concentrations of 9–10 g/dl on LVM index and did not clearly affect the development or progression of LVH [13]. Furthermore, in another clinical trial designed to assess whether the prevention and/or correction of anaemia by immediate (Hb target level of 12.0–14.0 g/dl) vs delayed (Hb target level of 9.0–10.5 g/dl) treatment with epoetin-{alpha} in patients with CKD would retard LV growth, there was no statistically significant difference between groups for the primary outcome of mean change in LVM index from baseline to 24 months [14]. From their study results, the authors concluded that observed and randomly assigned Hb level and LVM index are not linked, and thus, there is strong evidence that the association between Hb level and LVM index likely is not causal [14]. Another recently reported open-label, randomized, parallel-group study (CREATE) in patients with mild to moderate anaemia and stages 3–4 CKD investigated the effect of early anaemia correction by epoetin-ß on cardiovascular risk reduction, including LVM, progression of renal disease and quality of life in patients not yet requiring renal replacement therapy. At baseline and study end, there were no significant differences between the groups, although when patients were grouped by LVM index ranges at baseline, significant reductions in LVM indices after 1 year and 2 years were observed; the observed stabilization and/or regression of LVH was considered to have resulted from anaemia treatment [15].

This prospective intervention study examined whether epoetin-{alpha} therapy in predialysis CKD patients at an early stage in the development of their anaemia could offer an improved health status without adding other health concerns, compared with intervention once patients were already significantly anaemic. The study, which began in 1997, was stopped early (December 2002) by the sponsor due to contraindication of the subcutaneous route of administration for epoetin-{alpha} (patients in this study had received epoetin-{alpha} via the subcutaneous route before contraindication of this route of administration). Patients were followed-up for reasons of safety after their discontinuation, and were subsequently continued on a different epoetin preparation to maintain their well-being. The results presented here provide some of the final available trial data in CKD patients administered epoetin-{alpha} by the subcutaneous route before discontinuation of the study.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
 References
 
Patient selection
Patients aged 18–85 years were required to have a diagnosis of progressive renal failure and were thought likely by the investigator to require dialysis within 1–5 years of study enrolment. Each patient had to have a serum creatinine level of 150–500 µmol/l and an Hb concentration of 11.0 ± 0.5 g/dl, with no evidence of iron deficiency (i.e. serum ferritin ≥60 µg/l, transferrin saturation ≥20%, and hypochromic red cells <10%). From baseline values of 150–500 µmol/l for creatinine and 11.0 ± 0.5 g/dl for Hb, both creatinine and Hb concentrations had to be considered to be deteriorating (Hb lower and creatinine higher than the preceding reading), as determined by a series of three readings over at least 3 months before enrolment.

Excluded were patients who had previously received renal replacement therapy (including renal transplant), those with unstable or poorly controlled angina or severe congestive cardiac failure (New York Heart Association Grade III or IV), gross cardiomyopathy/LVH (as evidenced by screening echocardiogram), surgically placed arteriovenous fistula, poorly controlled hypertension (>160/90 mmHg), severe chronic respiratory disease, severe symptomatic peripheral vascular disease (‘severe’ as determined by the investigator), or those in whom LVM could not be deduced from an echocardiogram. Nor were they allowed to have haemoglobinopathies, marrow disorders or other conditions known to cause anaemia, inflammatory or infectious diseases which might impair the response to erythropoietin, prior treatment with erythropoietin or blood transfusion, or to have taken androgens or erythropoiesis-suppressing medications within 1 month of enrolment or blood transfusion for other reasons within 3 months of enrolment. Women who were pregnant, lactating or without adequate contraception were also excluded.

Study design
Patients were recruited over 3 years to this randomized, prospective, open-label, comparative group trial at 24 sites in the UK. Each subject gave written informed consent before inclusion. The study was carried out in accordance with the Declaration of Helsinki (Hong Kong 1989) and its subsequent revisions, and was approved by Local Research Ethics Committees.

Patients were randomized using central randomization procedures (ClinPhone) to group A or group B. A previous survey of pre-dialysis patients (creatinine concentration 150–500 µmol/l) was used to review the natural history of the rate of decline of haemoglobin in those patients who exhibited progressive anaemia. Since 50% of patients who had a Hb of 11 ± 0.5 g/dl showed a fall in Hb to ≤9/dl within 2 years [16], a 1:2 randomization of group A:group B was employed. This was to ensure that over a maximum period of 2 years equal numbers of patients receiving study medication could be realized in each of the two groups. Patients in group A started subcutaneous epoetin-{alpha} (1000 U twice weekly) at an early stage of their anaemia (at randomization on day 1) in order to maintain their Hb concentration at 11.0 ± 1.0 g/dl. Those in group B were monitored every 2 months until their Hb concentration had fallen to a trigger level of ≤9.0 g/dl. Group B began treatment with SC-EPO (2000 U three times weekly) when their Hb level had remained at ≤9.0 g/dl for 3 months or had fallen to ≤8.0 g/dl on two consecutive occasions ≥2 weeks apart, or they developed clinical symptoms of anaemia. Hb concentration was subsequently maintained at 11.0 ± 1.0 g/dl. Epoetin-{alpha} was titrated at 1000 U weekly in both groups to maintain target Hb levels, and patients continued the study until 3 years or the start of renal replacement therapy or death.

The study design with the two randomized treatment groups, group A and group B, is shown in Figure 1.


Figure 1
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  		Fig. 1. Study design.

 
Subjects were withdrawn from the study at the investigators’ discretion, if any serious adverse events occurred, or if consent was withdrawn. The study was stopped early by the sponsor because of a label change.

Assessment procedures
Medical history, haematology, serum biochemistry and iron status, glomerular filtration rate (GFR), electrocardiogram and echocardiogram were assessed at screening.

LVM was calculated from an echocardiogram (Box 1). The primary efficacy variable was the greatest (worst) LVM. The greatest (worst) LVM and the change from baseline to greatest LVM, and the times to worst echo and to final echo were determined for each patient.


Box 1: Derivations from echocardiography

Systolic Function

Left ventricular dimensions were recorded from left parasternal long axis view with the M-mode cursor by the tips of mitral valve leaflets. At least three consecutive cardiac cycles were recorded with a simultaneous ECG, on a paper speed of 100 mm/s. Using leading edge methodology, end-diastolic dimension (EDD) was measured at the onset of the Q wave of the ECG, and end-systolic dimension (ESD) was measured at the end of the T wave, peak systolic inward movement. Left ventricular posterior wall and septal thickness were taken at the end-systole and end-diastole, using the same landmarks.

Fractional shortening was calculated using the equation:

Formula

Septal and posterior wall thickening fraction was calculated as:

Formula

Ejection fraction was estimated using the cube formula:

Formula

Left Ventricular Mass (LVM)

Measurements of the LVM were according to the Penn convention method.

LVM = 1.04 [(EDD + PWTD + IVSTD)3 – (EDD)3] – 13.6 g

                (PWTD is posterior wall thickness in diastole; IVSTD is inter-ventricular septal thickness in diastole).

Diastolic function

Transmitral Doppler flow velocities were recorded from the apical 4-chamber view with the sample volume positioned at the tips of mitral valve leaflets. Similar recordings of aortic flow velocities were obtained from the apical 5-chamber view with the sample volume proximal to the aortic valve cusps.

Measurements:

- peak early ‘E’ and late ‘A’ diastolic flow velocities and E/A ratio.
- E wave deceleration time, taken from the peak to exponential deceleration limit of the E wave.
- Doppler isovolumic relaxation as the time interval between end-systolic (from the aortic Doppler trace) and onset of transmitral E wave.
- Any detectable mitral regurgitation using continuous wave Doppler.

 

Secondary efficacy variables included progression of renal failure (measured by serial blood creatinine measurements, creatinine clearance and yearly isotopic GFR measurement using 51chromium-labelled EDTA), exercise tolerance and final epoetin-{alpha} doses. The number of patients who withdrew because of starting dialysis or death was recorded, and the time to dialysis or death from randomization was summarized using Kaplan–Meier plots and compared between the groups. In addition, the time to dialysis or death from the start of treatment was evaluated and compared. Exercise tolerance before treatment and at 1-year intervals were assessed from the distance walked in 6 min (performed twice, second recording used for analysis). Mean last recorded scores and mean worst (shortest) scores were compared between treatment groups.

Statistical analysis
The sample size was based on the ability to detect differences between degrees of LVH, as measured by worst LVM. Assuming a mean ± SD LVM of 200 ± 60 g in group A, 36 patients per group were required to detect an increase to 240 g in group B (5% significance level; two-sided test; 80% power). A 2:1 (group A:group B) randomization was employed so that equal numbers of patients receiving epoetin-{alpha} could be realized over a maximum period of 2 years, as detailed above. It was estimated that 40% of patients would leave the study due to the start of renal replacement therapy within 12 months of enrolment; therefore, a total of 70 patients in group A and 140 patients in group B were to be recruited.

A total of 197 patients were randomized into the study. The safety population comprised all the 197 patients (group A, n = 65; group B, n = 132). One patient (randomized in error to group A) with missing data was excluded from the intent-to-treat population.

The primary efficacy end point was the greatest (worst) LVM, which was compared using the Mann–Whitney U-test (after applying the Shapiro–Wilk test for normality). The numbers of patients in each group who withdrew because of dialysis or death were compared using the chi-squared test. Between-group comparisons of time to dialysis or death were made using the log rank test. The mean last recorded exercise tolerance scores and worst recorded scores were compared using the unpaired t-test, and the unpaired t-test was also used to compare changes in laboratory investigations. Haemoglobin was summarized and compared at each time point using the unpaired t-test. Area under the curve (AUC) was summarized up to month 12 and up to month 24, and compared at each time point using the unpaired t-test.

Weekly study medication usage was calculated for the time points years 1, 2 and 3, and compared using the Mann–Whitney U-test (after applying the Shapiro–Wilk test for normality). The final dose of study medication was calculated.

Statistical tests were interpreted at a 5% significance level (two tailed).



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
 References
 
Patient characteristics
From the 315 patients recruited from 24 centres, a total of 197 patients were randomized (group A, n = 65; group B, n = 132). Fifty-five patients in group B progressed to treatment.

Demographic details were similar between the groups (Table 1). The mean age for group A was 55.6 ± 13.6 years and for group B 54.5 ± 14.4 years; the proportion of males was 64 and 62% for the two groups, respectively. The stage of CKD at study enrolment was equally distributed among the groups, the majority of patients having CKD stage 3 or worse.


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  		Table 1. Patient baseline demographic, clinical and biochemical data

 
The majority of patients had a medical history of cardiovascular problems (group A, 95.3% vs group B, 92.4%); 92.2% in group A and 90.9% in group B had hypertension, and 10.9% in group A and 12.1% in group B had ischaemic heart disease (Table 1). Angiotensin-converting enzyme inhibitors were the most common type of medication prescribed before the study start (group A, 69.2% vs group B, 53.0%). A similar proportion of patients had diabetes (group A, 23.4% vs group B, 22.0%). During the study, the most common type of medication prescribed was iron preparations; oral iron was given to 56.3% of patients in group A and 59.8% of patients in group B, and intravenous iron was required by 28.1% in group A and 25.8% in group B (including some patients who required both preparations at different times during the study).

Study treatment (dose of epoetin-{alpha})
Study treatment began on day 1 for group A. The mean (±SD) time to trigger initiation of epoetin therapy (i.e. when Hb fell to ≤9 g/dl) for group B (n = 55) was 13.2 ± 7.9 months.

The total administered dose of epoetin-{alpha} to group A was 190 211 ± 127 216 U and to group B 152 146 ± 139 951 U. Epoetin-{alpha} dose over time is presented in Figure 2.


Figure 2
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  		Fig. 2. Dose of epoetin-{alpha} over time. Safety population (group A vs group B). Data are presented graphically using ‘box and whisker’ plots. The ‘box’ represents the interquartile range (25th to 75th percentiles), which contains 50% of the data, the mean (symbol) and median (line); + represents data that lie outside the upper or lower fences (either 1.5 times the inter-quartile range above or below the 75th and 25th percentiles, respectively); {diamondsuit} group A mean; • group B mean.

 
The mean weekly epoetin-{alpha} dose at 1 year was 1471 U in group A and 820 U in group B (Table 2). The difference between the doses was large at all 3 yearly time points. The final doses were 2281 U for group A and 2099 U for group B. These data were not normally distributed and, visually, the dispersions of the distributions are quite different for each group; further analyses of these data were considered not to be of value.


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  		Table 2. Annual weekly dose of epoetin-{alpha}

 
Discontinuations
A total of 118/315 patients failed the inclusion/exclusion criteria and were excluded at screening. Of the 197 patients randomized, 156 patients withdrew from the study prematurely (44, 68% in group A, 112, 85% in group B), and 20 patients in each group completed the study (data missing for one patient) (Figure 1). Patients in groups A and B withdrew from the study mainly due to commencement of dialysis (group A, 29 vs group B, 61) (Table 3).


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  		Table 3. Reason for and mean time to withdrawal from the study

 
Mean (±SD) time to completion or withdrawal from the study was 24.1 ± 10.8 months for group A and 21.1 ± 10.8 months for group B.



   Evaluation of efficacy
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
 References
 
Haemoglobin concentrations
For Hb concentrations at each time point, group A vs group B were significantly different at months 4 (P < 0.001), 8 (P < 0.001), 12 (P < 0.001), 16 (P < 0.001), 20 (P < 0.002), 24 (P < 0.001), 28 (P < 0.021) and at final visit (P < 0.007) (Figure 3). Mean (±SD) Hb AUC was also statistically different between groups A and B up to month 12 (group A, n = 51, 4260 ± 266; group B, n = 99, 3984 ± 361; P < 0.001) and from baseline up to month 24 (group A, n = 31, 8638 ± 353; group B, n = 53, 8068 ± 550; P < 0.001). However, the changes in Hb from baseline to final visit between the groups were not statistically significant (Table 4).


Figure 3
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  		Fig. 3. Haemoglobin concentration over time. Safety population (group A vs group B). Data are presented graphically using ‘box and whisker’ plots. The ‘box’ represents the interquartile range (25th to 75th percentiles), which contains 50% of the data, the mean (symbol) and median (line); + represents data that lie outside the upper or lower fences (either 1.5 times the inter-quartile range above or below the 75th and 25th percentiles, respectively); {diamondsuit} group A mean; • group B mean. The number of patients who had triggered (in group B) at each time point is 5, month 4; 15, month 8; 18, month 12; 18, month 16; 14, month 20; 13, month 24; 15, month 28; 12, month 32; and 5, month 36. Group A vs group B were significantly different at months 4 (P < 0.001), 8 (P < 0.001), 12 (P < 0.001), 16 (P < 0.001), 20 (P = 0.002), 24 (P < 0.001), 28 (P = 0.021).

 

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  		Table 4. Change from baseline to final visit in haemoglobin concentrations, serum creatinine concentrations and creatinine clearance

 
Primary efficacy variable
There were no statistically significant differences in the changes from baseline to final visit for either treatment group. However, there was a trend to reduction in LVM with time and in the change from baseline to worst result in group A (Table 5). There was a tendency for LVM for patients in group B to be lower at 24 months than at the final visit, probably because the final visit was often before month 24 for the high number of patients who withdrew from the study. There were no statistically significant differences between the groups for worst LVM or last recorded LVM.


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  		Table 5. Left ventricular mass (LVM)

 
Secondary efficacy variables
Progression of renal failure
Similar proportions of patients in groups A and B withdrew from the study for reasons of dialysis or death (31, 48% group A; 68, 52% group B; P = 0.686). One patient in group A and five in group B died; one patient in group B withdrew from the study for dialysis and later died. Absolute mean (±SD) time to dialysis or death from randomization was 16.2 ± 8.4 months for group A and 16.4 ± 8.7 months for group B; this calculation did not take into account the premature study terminations for other reasons. Although not statistically significant, Kaplan–Meier estimates indicated that group A had a tendency to longer median time to dialysis or death than group B (36.3 vs 27.3 months) (Table 6, Figure 4).


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  		Table 6. Patients and time to dialysis or death

 

Figure 4
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  		Fig. 4. Time to dialysis or death (Kaplan–Meier). Intent-to-treat population (group A vs group B). — group A; ...... group B.

 
Exercise tolerance
In the last recorded exercise tests, the mean (±SD) distance walked in 6 min was comparable between the groups (419.3 ± 124.4 m for group A, 420.5 ± 129.0 m for group B; P = 0.954). There were no significant differences between the groups when their worst exercise tests were compared (395.8 ± 110.5 m for group A, 408.4 ± 127.8 m for group B; P = 0.526).



   Evaluation of safety
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
Discussion
 Appendix
 Acknowledgements
 References
 
Renal function and other laboratory measurements
The changes over time in creatinine concentrations, creatinine clearances and isotopic GFR measurements from baseline to final visit are shown in Table 4 and Figure 5. Between group comparisons of the changes from baseline to final visit in serum creatinine concentrations, and creatinine clearance were not statistically significant (Table 4). There were also no significant differences in other laboratory measurements.


Figure 5
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  		Fig. 5. Measurement of renal function over time: 51Cr-EDTA GFR (in number) and GFR (Cockcroft–Gault box plots). Safety population (group A vs group B). Data are presented graphically using ‘box and whisker’ plots. The ‘box’ represents the interquartile range (25th to 75th percentiles), which contains 50% of the data, the mean (symbol) and median (line). + represents data that lie outside the upper or lower fences (either 1.5 times the inter-quartile range above or below the 75th and 25th percentiles, respectively); {diamondsuit} group A mean; • group B mean

 
Adverse events
There was a high number of adverse events reported, reflecting the length of the study and the comorbidity burden of the patients (Table 7). Seven patients died; one in group A and six in group B. The number of patients reporting adverse events was 62 (95.4%) in group A and 126 (95.5%) in group B. The most commonly reported drug-related adverse events were hypertension [group A, four (6.2%) patients; group B, one (0.8%) patient] and aggravated hypertension [group A, three (4.6%) patients; group B, three (2.3%) patients]. Two patients in group B had adverse events considered both serious and drug-related (haematemesis, pure red cell aplasia). There were no changes of significance in vital signs in groups A or B.


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  		Table 7. Adverse events

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
Appendix
 Acknowledgements
 References
 
This prospective, randomized, comparative group trial examined the potential value of epoetin-{alpha} therapy in pre-dialysis CKD patients at an early stage in the development of their anaemia compared with intervention once patients were already significantly anaemic. There were no ‘best practice’ guidelines at the time of creating the study protocol in 1997. Historical review of CKD patients had shown that approximately 50% of such patients whose baseline Hb and creatinine concentrations suggest that their Hb concentrations are likely to fall to 9 g/dl before receiving renal replacement therapy will do so within 6–24 months of reaching a Hb of 11.0 ± 0.5 g/dl [16]. However, although European guidelines now recommend that treatment should begin in renal patients whose Hb concentrations are 11.0 g/dl [17], treatment is often delayed in everyday clinical practice. The aim of this study embraced evaluation of the effects of a delay in starting treatment. The study had to be stopped early by the sponsor due to contraindication of the subcutaneous route of administration but, on discontinuation of the study, patients were continued on a different epoetin preparation to maintain their well-being.

Unfortunately, and in light of current knowledge, some limitations to this study protocol are evident, due to the fact that it was designed over 8 years ago. In hind-sight, planning and design should have allowed comparison of group A, group B, those patients in group B who remained untreated and those in group B that were treated—if only to indicate the value of some form of treatment intervention. Additionally, using the worst echo is now considered to be unacceptable as the follow-up may differ for the two groups.

Patient groups were well-matched at study start, including their stage of CKD. There was a high rate of discontinuation during the study. This was expected as the study enrolled pre-dialysis CKD patients who had demonstrated declining Hb concentrations and who had reached an Hb concentration of 11.0 ± 0.5 g/dl while creatinine concentrations were between 150 and 500 µmol/l. The main reason for study discontinuation was commencement of dialysis.

Clinical trials have demonstrated the effectiveness of epoetin-{alpha} in increasing Hb levels in iatrogenic and disease-related anaemias [18]. There was strong evidence to conclude that Hb concentration differed over time between patients treated early with epoetin-{alpha} and those in whom Hb concentration was allowed to fall to 9 g/dl or less before treatment commenced. As anaemia is an independent predictor of LVH [4], avoidance of anaemia might be expected to favourably affect LV growth among patients with advanced CKD. Although not randomized controlled trials, a few small studies of dialysis patients have shown that normalizing Hb levels provides benefits in terms of reductions and possibly prevention of LVH [6–8]. The results of the intention-to-treat analysis reported here were negative; this study did therefore not indicate a significant benefit in terms of LVH by treating patients early in the development of anaemia rather than at a late stage, although LVM showed a tendency to decrease with early correction of Hb levels. Premature termination, resulting in fewer patients completing the study than planned, may have limited the impact of treatment reaching statistical significance. The result may also be partially due to the limited separation of Hb levels between the groups, and a longer follow-up period might have been required.

The lack of a significant difference in LVM is similar to that found in the study by Roger et al. [13], which compared patients in whom treatment was initiated to maintain Hb concentrations above 12 g/dl (early treatment) with patients in whom treatment was initiated when Hb concentration had fallen to ≤9 g/dl (late treatment) and maintained at 9 to 10 g/dl. The latter was also attributed to the maintenance of Hb concentrations above 10 g/dl for many patients in the late treatment group. The findings of the latter study did not indicate a clear benefit for maintenance of nearly physiological Hb; there was a slight absolute decrease and rate of decrease in Hb values in the late treatment group, and the intergroup differences in Hb, although statistically significant, were considered to be of marginal clinical significance [13]. Furthermore, lack of statistical significance in the mean change in LVM index was found in another clinical trial designed to assess whether the prevention and/or correction of anaemia, by immediate (Hb target level of 12.0–14.0 g/dl) vs delayed (Hb target level of 9.0–10.5 g/dl) treatment with epoetin-{alpha} in patients with CKD would delay LV growth [14]. There was also no statistical difference between the groups in absolute values nor in the number of patients with LV growth. However, where mean LVM index did not change in patients with a stable Hb level, it significantly increased in those with decreasing Hgb levels. The authors concluded that observed and randomly assigned Hb level and LVM index are not linked, and thus, there is strong evidence that the association between Hb level and LVM index likely is not causal [14].

In this study, there was neither a significant difference in the number of patients progressing to renal failure or death nor in the median time taken for this to occur, when patients who were treated early with epoetin-{alpha} were compared with those who were treated at a later stage in the development of their anaemia. Any apparent divergence in Hb concentration over time between the groups was not significant by the end of the study. These data have assumed greater importance in the last few years with the realization that erythropoietin has many extra-erythropoietic effects as an apoptotic agent in non-haemopoietic cell types [19], and it has thus been hypothesized that epoetin could influence the progression of renal impairment via this mechanism, in addition to its effects on haemoglobin [20].

Within the late treatment group, there was evidence that patients who progressed to severe anaemia progressed much more rapidly in terms of both renal failure and anaemia than patients who maintained their Hb above 9 g/dl without epoetin-{alpha}. Thus, defining the characteristics of the subgroup of patients at baseline who are likely to have the greatest subsequent decline in Hb, and selecting these patients for further studies, would be expected to provide the most robust data on the value of ‘early’ treatment of anaemia with epoetin. In this study, the time for renal patients to reach the Hb trigger level of <9 g/dl was found to be around 13 months, which is considered to be the approximate length of time seen in clinical practice before they require dialysis. A recent randomized controlled trial also investigated the optimal timing of initiation of epoetin-{alpha} treatment in pre-dialysis patients with non-severe anaemia using a similar regimen of early treatment (Hb 9.0–11.6 g/dl) and deferred treatment (Hb fallen to <9 g/dl) [21]. Early initiation of epoetin-{alpha} significantly slowed the progression of renal disease and delayed the start of renal replacement therapy; the reduction in the risk of initiation of renal replacement or death was 60% [21].

Prevention or correction of anaemia may impart other benefits, and an increase in Hb concentration has been associated with generally improving fatigue symptoms and enhancing overall quality of life [18]. Normalizing Hb levels in dialysis patients has previously demonstrated benefits to well being and quality of life [10,11]. In a study specifically investigating the effect of Hb levels on exercise capacity, physiological Hb levels improved performance in ESRD patients [12]. However, exercise performance generally remained below predicted levels for age-matched sedentary controls, and the likelihood is that other variables contributed to the observed limitations. In our study, wide variation in scores for worst exercise tests possibly precluded any difference between the groups for the distance walked in 6 min. Although some variables between the groups were ruled out at screening (e.g. concurrent disease), others, such as inactivity of patients, may have influenced the results.

Data on the total and mean weekly dose of epoetin in the groups receiving treatment early or late in the development of their anaemia were not considered suitable for useful statistical analysis. The raw data suggested that final mean weekly doses in each group were similar. Comparative epoetin dose requirements for patients receiving treatment for their anaemia early or late, merit further investigation. Should any significant difference in dose requirements be demonstrated, this would infer considerable cost savings.

There is a growing awareness that anaemia correction has the potential to substantially improve clinical and reported outcomes. In this study, early intervention to correct anaemia in patients approaching ESRD did not significantly impact on LVM or 6-min walking distance. Further intention-to-treat studies are required to evaluate the effects of a fall in Hb to <9 g/dl by comparing patients who progressed to severe anaemia with patients who maintained their Hb above 9 g/dl without epoetin.



   Appendix
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
Acknowledgements
 References
 
The EPO-GBR-2 Study Group comprised the following investigators and Renal Units in the UK: Dr DN Bennett-Jones, Cumberland Infirmary, Carlisle; Dr J Bradley, Addenbrooks Hospital, Cambridge; Dr EA Brown, Charing Cross Hospital, London; Dr A Burns, Royal Free Hospital, London; Prof. R Cove-Smith, James Cook University Hospital, Middlesbrough; Dr C Daly, Aberdeen Royal Infirmary, Aberdeen; Dr K Farrington, Lister Hospital, Stevenage; Dr GR Glancey, Ipswich Hospital, Ipswich; Dr A Heaton, Norfolk and Norwich University Hospital, Norwich; Dr R Higgins, Walsgrave Hospital, Coventry; Dr A Hutchison, Manchester Royal Infirmary, Manchester; Dr C Kingswood, Royal Sussex County Hospital, Brighton; Dr J Kwan, St Helies Hospital, Carshalton; Dr I Macdongall, King's College Hospital, London; Dr RB Naik, Royal Berkshire Hospital, Reading; Dr P Naish, Royal Infirmary, Hartshill, Stoke-on-Trent; Dr CG Newstead, St James’ University Hospital, Leeds; Dr A Palmer, St Mary's Hospital, London; Dr M Raftery, Royal London Hospital, London; Dr P Rowe, Derriford Hospital, Plymouth; Dr L Sellars, Hull Royal Infirmary, Hull; Dr JS Tapson, The Freeman Hospital, Newcastle Upon Tyne; Dr RM Temple, Heartlands Hospital, Birmingham; Dr CRV Tomson, Southmead Hospital, Bristol.



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
References
 
We would like to thank Katherine Hutchinson for the statistical analysis and Dr Sue Libretto for assistance in the preparation of the manuscript. This study was funded by Ortho Biotech (a division of Janssen-Cilag).

Conflict of interest statement. This study was funded by Ortho Biotech (a division of Janssen-Cilag). Consultancy fees were received from Ortho Biotech (Janssen-Cilag) by the authors in their role as members of the EPO-GBR-2 Steering Committee.

(See related article by Roger and Levin. Epoetin trials: randomized controlled trials don’t always mimic observational data. Nephrol Dial Transplant 2007; 22: 684–686.)



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Evaluation of efficacy
 Evaluation of safety
 Discussion
 Appendix
 Acknowledgements
 References
 

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Received for publication: 27. 9.04
Accepted in revised form: 18. 7.06


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Epoetin trials: randomised controlled trials don't always mimic observational data
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