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
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Abstract |
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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
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Introduction |
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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 1530%. 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.
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Subjects and methods |
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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.
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Statistical analysis |
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Comparisons between treatment groups were carried out using 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).
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Results |
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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 2). 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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Mean serum ferritin levels were lower in the once weekly group than in controls. This difference remained at 22 weeks (Table 3), however this was not statistically significant. Transferrin saturation values were similar in both groups at baseline, and again within-group differences from weeks 022 were not statistically significant.
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Discussion |
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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.
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Acknowledgments |
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Notes |
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References |
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