The efficacy of once weekly compared with two or three times weekly subcutaneous epoetin ß: results from a randomized controlled multicentre trial

on behalf of the Swedish Study Group

Lars G. Weiss1,, Naomi Clyne2, Jose Divino Fihlho3, Carsten Frisenette-Fich4, Jan Kurkus5 and Birgitta Svensson6

1 Department of Nephrology, Centralsjukhuset, Karlstad, 2 Department of Nephrology, Karolinska Hospital, Stockholm, 3 Dialysis unit, Sophiahemmet Hospital, Stockholm, 4 Department of Medicine, Länssjukhuset Ryhov, Jönköping, 5 Department of Nephrology, Universitetssjukhuset, Lund, 6 Clinical Study Service AB, Box 410, S-681/28 Kristinehamn, Sweden



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
Background. Anaemia in haemodialysis patients can be effectively treated with erythropoietin. We investigated whether subcutaneous (SC) epoetin ß administered once weekly was as effective as the same weekly dosage given in two to three divided doses.

Methods. One hundred and fifty-eight patients (delivered Kt/V >1.0, where K=dialyser-renal urea clearance, t=dialysis time and V=filtration volume, obtained by urea kinetic modelling) were randomized to treatment with SC epoetin ß either once weekly (n=118), or to their original dosage two or three times weekly (control group, n=40) for 24 weeks. All patients received intravenous iron supplementation when necessary.

Results. Eight-eight patients in the once weekly group and 30 patients in the control group were treated for at least 16 weeks and are included in the analysis. Stable haemoglobin levels were maintained without epoetin dose increases in 73% of patients in both groups. Mean haemoglobin levels at randomization and after 16 and 24 weeks were 11.4, 11.1 and 11.1 g/dl, respectively, in the once weekly group compared with 11.2, 11.3 and 11.2 g/dl, respectively, in the control group. The mean weekly epoetin ß dosages at randomization and after 16 and 24 weeks were 102, 103 and 106 IU/kg bodyweight, respectively, in the once weekly group compared with 109, 109 and 115 IU/kg bodyweight, respectively, in the control group. No statistically significant between-group differences were apparent for changes in haemoglobin levels or epoetin ß dosages at week 24.

Conclusions. Once weekly SC administration of epoetin ß is as safe and effective in maintaining haemoglobin levels in stable haemodialysis patients as two or three times weekly administration of the same total dose. By using the once weekly regimen, patients can avoid up to 104 injections per year. This would reduce clinic time for patients who do not self administer, and may also encourage self-administration and improve overall compliance.

Keywords: epoetin beta; renal anaemia; subcutaneous



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
Erythropoietin (Epo; epoetin) has been used for treatment of renal anaemia in haemodialysis patients for more than a decade [1], and has had a major impact on the quality of life of these patients [2], reducing fatigue and increasing physical exercise capacity.

Multicentre studies performed both in the USA and Europe have shown that treatment with intravenous (IV) Epo three times weekly is effective and safe [3,4]. Bommer et al. suggested that smaller doses given subcutaneously (SC) produced similar haemoglobin levels to higher doses given IV [5,6], despite the fact that bioavailability of Epo following SC injection is only 15–30%. This has been confirmed by a US multicentre trial involving 208 patients, which showed a 32% reduction in Epo requirement in patients given SC treatment three times weekly [7]. Moreover, Parker et al. [8] showed that a haematocrit of 31% could be sustained with once weekly SC Epo at only one third of the usual total weekly IV dose. However, other reports have shown only minor [9] or no advantages [10] of SC vs IV Epo administration.

Initially it was assumed that daily SC administration of epoetin ß would lead to a lower total weekly epoetin ß dose [11]. Later studies, however, demonstrated no clinically relevant difference in total dose per week for SC epoetin ß given daily or three times weekly [12]. In continuous ambulatory peritoneal dialysis (CAPD) patients, SC epoetin ß administered once weekly has been shown to be effective [13].

Patients' iron status has an important effect on individual response to Epo treatment [14]. It has been shown in a randomized controlled study that even in iron-replete patients, those supplemented with IV iron have an enhanced haemoglobin response to Epo and thus require lower doses [15]. Another important factor affecting the response to a given Epo dose is the amount of dialysis given. It has been shown that while keeping the Epo dose constant, significant increases in haematocrit result from increasing the delivered dialysis dose [16,17].

The aim of this study was to investigate whether SC epoetin ß, as a maintenance dose once weekly, was as effective as the same total SC dose administered two or three times weekly in patients undergoing chronic haemodialysis treatment.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
This study was conducted as an open-label, randomized, controlled multicentre study using two parallel groups. The study design is presented schematically in Figure 1Go. Patients were enrolled from 15 dialysis centres and were randomized into the study by a central randomization centre. Patients were stratified for sex and age (18–55 years and 56–80 years). All patients gave written, informed consent. The study was conducted according to the Nordic guidelines for Good Clinical Practice, and was approved by the Ethics Committee in Örebro, in affiliation with the medical faculty of Uppsala University.



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Fig. 1. Study design.

 
Inclusion and exclusion criteria were evaluated at the start of the 8-week pre-study period and at week 0. If serum ferritin at the beginning of the pre-study period was <200 µg/l, 100 mg IV iron saccharate was given at five consecutive dialysis sessions. This was followed by a maintenance dose of 50 mg IV iron saccharate once weekly or 100 mg every other week. If serum ferritin was still <200 µg/l 2 weeks after the loading dose, a further dose to a total of 500 mg iron saccharate was given. Maintenance treatment with iron saccharate was continued during the 24-week period in both groups if serum ferritin levels continued to be <500 µg/l.

Inclusion criteria were: patients aged between 18 and 80 years on regular haemodialysis treatment two or three times weekly; treatment with SC epoetin ß two or three times weekly with a stable haemoglobin level between 10.0 and 12.5 g/dl in the 8-week pre-randomization period; an adequate iron status defined as serum ferritin >200 µg/l and/or transferrin saturation >20%; and delivered Kt/V >1.0 (K, dialyser-renal urea clearance; t, dialysis time; V, filtration volume). Exclusion criteria were: uncontrolled hypertension (defined as diastolic blood pressure >100 mmHg); serum aluminium >100 µg/l; vitamin B12 (<100 ng/l) or folic acid (<3.0 µg/l) deficiency; ongoing infection; known epilepsy; known hyperparathyroidism (where surgery might be considered); and pregnancy or lactation.

Prescribed Kt/V for one single dialysis was calculated from K, t and V, obtained by urea kinetic modelling [18]. Outcome Kt/V was calculated by the Daugirdas method [19], based on the reduction in the serum urea concentration during dialysis and taking the effect of ultrafiltration into consideration. The results with the two methods were similar, so we present here outcome Kt/V only since its calculation is independent of technical artefacts. The contribution of renal urea clearance was added to K in patients who had residual renal function (renal urea clearance >0.5 ml/min). If there was a change in the dialysis prescription in order to meet the inclusion criteria, a new Kt/V was measured.

Patients were randomly assigned to either once weekly SC epoetin ß (NeoRecormon®; F. Hoffmann-La Roche, Basel, Switzerland), or to their original two or three times weekly administration regimen, in a 3 : 1 ratio. Epoetin ß was injected into the thigh or abdominal area, according to the patient's previous experience, and the site of injection remained unchanged throughout the study. The dose of epoetin ß used is presented as IU/kg bodyweight (BW) post-dialysis. Six weeks after randomization, a 20% increase in the epoetin ß dose was allowed if serum haemoglobin was <10.0 g/dl and had decreased >1.0 g/dl from the mean value of the last two pre-randomization haemoglobin levels. Thereafter, the current dose could be increased by 20% every fourth week, according to the aforementioned criteria. The epoetin ß dose was reduced by 20% if a haemoglobin level >13.0 g/dl was recorded and had increased by >1.0 g/dl compared with the pre-randomization mean value.

The following variables were measured in all subjects: (i) every other week, haemoglobin and haematocrit (blood was drawn midweek, prior to the dialysis session); (ii) every month, platelets, leucocytes, mean corpuscular volume and haemoglobin concentration, serum sodium, potassium, calcium and albumin, liver transaminases, alkaline phosphatase, bilirubin and C-reactive protein; and (iii) every 8 weeks, serum iron and ferritin, transferrin saturation and parathyroid hormone (PTH).

The primary efficacy variable was the proportion of patients who maintained a stable haemoglobin level without requiring an increase in total weekly dose. Secondary outcome variables were mean haemoglobin level and epoetin ß dose. Safety variables assessed were general and local tolerance to epoetin ß, blood pressure, adverse events and the number of withdrawals from the study.



   Statistical analysis
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 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
It was estimated that a sample size of 30 patients in the control group and 90 patients in the once weekly regimen would enable 80% power to detect an increase of 20 percentage points in the proportion of patients requiring dose adjustment (20% in the once weekly group and 1% in the control group). This sample size was also sufficient to detect small differences in mean haemoglobin between treatment groups. Assuming a within-group standard deviation of 1.0 g/dl, these patient numbers were sufficient to give the study a power of 80% to detect a difference between group means of 0.6 g/dl. To allow for withdrawals, target recruitment was set at 160 patients.

Comparisons between treatment groups were carried out using {chi}2 test to assess whether there was any significant difference between groups in the number of patients who maintained stable haemoglobin levels without increases in epoetin dose. A two-sample t-test was used to compare differences in haemoglobin levels and weekly epoetin ß dose. Interval estimates of differences between treatments are given as 95% confidence levels. A significance level of 5% was considered statistically significant. All calculations were carried out using the SAS System (version 6.10).



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
One hundred and fifty-eight patients were randomized, 118 to the once weekly group and 40 to the control group (who continued with their previous dose of epoetin ß two or three times weekly). Of the 118 patients randomized to once weekly administration, 61 had received epoetin ß twice weekly in the pre-study period and 57 had received the drug three times weekly. In the control group, 19 and 21 patients received epoetin ß two or three times weekly, respectively. The causes of renal failure in the randomized population were: chronic glomerulonephritis (34 patients), nephrosclerosis (24), interstitial nephritis (23), diabetes mellitus (18), polycystic kidney disease (14), systemic lupus erythematosus and other vasculites (9), other specific causes (17) and uraemia of unknown origin (19). Patient characteristics were similar between the two groups with respect to age, bodyweight and type of dialysis treatment. Mean (±SD) Kt/V values were 1.33±0.24 in the once weekly group compared with 1.39±0.35 in controls. There were more male than female patients in both treatment groups. Demographic data are given in Table 1Go.


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Table 1. Mean (±SD) demographic data

 
A total of 118 patients (88 in the once weekly group and 30 in the control group) completed at least 16 weeks of the study and were evaluated for efficacy. Thirty patients in the once weekly group (25%) and 10 controls (25%) were withdrawn from the evaluation prior to week 16 for the following reasons: protocol violation in 13 patients (haemoglobin level >12.5 g/dl at randomization (11), dose change in the pre-study period (1), and once weekly therapy at randomization (1)); death during study in 10 patients (congestive heart failure (4), rupture of aortic aneurysm (1), myocardial infarction (2), mediastinitis (1), paralytic ileus (1), and exacerbation of Wegener's granulomatosis (1)). Eleven patients were withdrawn owing to adverse events (10 were unrelated to epoetin ß treatment, and one was due to aggravation of hypertension and headache, possibly related to epoetin ß treatment). Six patients were withdrawn owing to kidney transplantation. In addition, two patients evaluated for efficacy were withdrawn after 16 weeks; one because of kidney transplantation and one died from withdrawal of dialysis therapy on patient's request. Patient disposition is summarized in Figure 2Go.



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Fig. 2. Patient disposition.

 
There was no statistically significant difference between groups in the number of patients who maintained stable haemoglobin levels without epoetin dose increases (P=0.949). Indeed, stable haemoglobin values were maintained without dose increases in 73% of patients in both groups during the 24-week study period (Figure 2Go). Of the 24 patients in the once weekly group requiring dose increases (12 of whom had received twice weekly and 12 had received three times weekly epoetin prior to randomization), seven required more than one dose increase. In the control group, one patient needed two increases, and another patient needed three dose increases. The epoetin ß dose was reduced in seven out of 88 (8%) patients in the once weekly group and in five out of 30 (17%) patients in the control group.

At randomization, the mean (±SD) haemoglobin level in the once weekly group was 11.4±0.6 g/dl compared with 11.2±0.6 g/dl among controls. There were no statistically significant differences in mean haemoglobin levels between groups at week 24 (Table 2Go). At week 24, the 95% confidence interval for the difference in mean haemoglobin levels between groups was 0.35±0.55 g/dl. Although not clinically significant, a statistically significant increase from baseline in mean haemoglobin levels was found at week 16 in the control group compared with the once weekly group (P=0.02). This difference was no longer present at the end of the study (week 24).


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Table 2. Mean (±SD) epoetin ß dose and haemoglobin level at baseline (week 0) and weeks 6, 16 and 24

 
At randomization and throughout the 24-week study period, the mean dose of epoetin ß per kg BW was slightly lower in the once weekly group compared with controls (Table 2Go). The changes in mean dose of epoetin ß between the two treatment groups for weeks 0–24 were not statistically significant.

Mean serum ferritin levels were lower in the once weekly group than in controls. This difference remained at 22 weeks (Table 3Go), however this was not statistically significant. Transferrin saturation values were similar in both groups at baseline, and again within-group differences from weeks 0–22 were not statistically significant.


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Table 3. Mean (±SD) serum ferritin level and transferrin saturation at baseline (week 0) and weeks 8, 14 and 22

 
Epoetin ß given once weekly was well tolerated, and there was no requirement for an increase in antihypertensive treatment compared with controls. No reports of pain at the injection site were recorded.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
These results show that SC epoetin ß can be given once weekly to stable haemodialysis patients in order to maintain a mean haemoglobin level between 11.0 and 11.5 g/dl. Although it might be expected that a reduction in dosage frequency would lead to a reduction in haemoglobin levels in the once weekly group, the virtually identical mean haemoglobin levels between groups at 24 weeks suggest that this does not occur. The 95% confidence interval of difference at week 24 clearly demonstrates that the once weekly regimen delivers equivalent long-term clinical efficacy. Moreover, these results show that this can be achieved without increasing the total weekly SC epoetin ß dose compared with a control group receiving two to three injections a week. The mean weekly maintenance dose of epoetin ß in this study after 24 weeks of treatment was 106 IU/kg BW in the once weekly group and 115 IU/kg BW in controls. This is only slightly higher than that found in the SC arm of a US study comprising 107 patients treated with three times weekly Epo, where the mean weekly dose was 95 IU/kg BW. However, mean haemoglobin levels were lower (10.4 g/dl) in the US study [7].

The 3 : 1 randomization ratio adopted in this study allowed an increased number of patients to be exposed to the new regimen, while retaining statistical power to detect clinically relevant changes in study parameters. This design has allowed an improved assessment of the safety profile for the once weekly schedule and is unlikely to have affected the overall outcome of the study. The groups were well balanced in terms of pre-study dosage schedules and mean haemoglobin levels, enabling reliable comparisons to be made.

Several factors can interfere with the response to Epo. Deficient iron status [15] is a well known factor that increases the required Epo dose. For this reason, iron status was carefully monitored during this study and the method of intravenous iron supplementation used, is in accordance with guidelines recently published by Drüeke et al. [20]. Use of intravenous iron probably contributed to the efficacy of once weekly SC administration in this study. Furthermore, low Kt/V values have been described as a potential factor that may increase Epo requirement [16,17]. For this reason, only well dialysed patients were included in this study. As described previously, both groups in this study had mean Kt/V values >1.3, ruling out deficient dialysis as a factor influencing Epo requirement. Polycystic disease is known to promote erythropoiesis, and may therefore also influence Epo requirements. However, in this study the number of patients with polycystic disease represented a small proportion (9%) of the total study population and is therefore unlikely to have affected overall Epo requirements.

Use of Epo among dialysis patients is widespread. In a survey of 1713 Swedish haemodialysis patients in 1998, for example, 1583 (93%) were on Epo therapy (unpublished observations, Swedish Society of Nephrology). Obtaining maximal response to Epo therapy must therefore be a primary aim, given the rising costs for healthcare. Compared with two to three times weekly administration, once weekly SC injection of epoetin ß achieves the same effect on the patients' haemoglobin levels and may free valuable nursing time in patients who do not self administer. For patients who self-administer their epoetin ß, the fact that injections are pain free and that fewer are required with once weekly administration (up to 104 fewer injections per year) may help patient compliance with medication.

In conclusion, these results show that once weekly SC epoetin ß administration is effective in maintaining target haemoglobin levels, and that it has a similar safety profile to that seen with a two or three times weekly regimen. In addition, once weekly administration reduces injections by at least one half, facilitating patient self-administration and reducing the workload in renal units. We therefore recommend that SC epoetin ß is given once weekly in stable haemodialysis patients.



   Acknowledgments
 
The authors express their gratitude to the following doctors and staff of the participating centres: Per-Ola Attman (Sahlgrenskasjukhuset, Göteborg), Brita Hylander (Karolinskasjukhuset, Stockholm), Finn David-Nielsen (Lasarettet, Borås), Unni Viidas (Bassjukhuset, Falköping), Mats Ekberg (Sjukhuset, Hässleholm), Lars Svensson (Höglandssjukhuset, Eksjö), Martin Magnusson (Lasarettet, Motala), Erik Hoffstedt (Lasarettet, Visby), Peter Barany (Huddingesjukhuset, Stockholm) and Jonas Berglund (Danderydssjukhuset, Stockholm).



   Notes
 
Correspondence and offprint requests to: Lars G. Weiss M. D. PhD, Department of Nephrology, Centralsjukhuset, S-651 85 Karlstad, Sweden Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 

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Received for publication: 21. 2.00
Revision received 28. 7.00.