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NDT Advance Access published online on September 22, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm579
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Darbepoetin alpha in lower-than-equimolar doses maintains haemoglobin levels in stable haemodialysis patients converting from epoetin alpha/beta

H. Andreas Bock1, Patricia Hirt-Minkowski2, Michel Brünisholz3, Gerald Keusch4, Simone Rey5, Beat von Albertini6 and for the Swiss EFIXNES trial investigators*

1Division of Nephrology, Kantonsspital Aarau, 2Regionalspital Emmental, Burgdorf, 3Hôpital regional, Porrentruy, 4Waid Spital, Zürich, 5PFC Pharma Focus Ltd, Volketswil and 6Clinique Cécil, Lausanne

Correspondence and offprint requests to: H. Andreas Bock, Division of Nephrology, Kantonsspital, Buchserstrasse, CH-5001 Aarau, Switzerland. Email: andreas.bock{at}ksa.ch



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Background. The conversion of patients on stable epoetin therapy to darbepoetin alpha is usually carried out according to the ‘1 µg darbepoetin = 200 U epoetin’ rule, which is based on the protein content of the two compounds. Since several observations have suggested that this conversion factor leads to an overestimate of the required darbepoetin dose, the present multicentre study was designed to assess the true conversion ratio by prospectively evaluating the change in darbepoetin alpha dose after conversion from epoetin, which was required to keep haemoglobin (Hb) stable.

Methods. Haemodialysis patients with stable Hb and maintained on either s.c. or i.v. epoetin (alpha or beta) were switched to intravenously administered darbepoetin alpha according to the 1:200 rule. Subjects treated with epoetin two or three times per week received one weekly dose of darbepoetin alpha, subjects on weekly epoetin received darbepoetin alpha every 2 weeks. For 20 weeks, darbepoetin alpha was changed every 2 weeks according to a pre-specified algorithm, if this was needed to keep Hb within ±1.0 g/dl of each subject's individual baseline. Thereafter, patients entered a 4-week evaluation period.

Results. One hundred ad thirty-two patients in 17 Swiss centres were enrolled and 100 completed the study throughout the evaluation period. While mean Hb was maintained stable between baseline and evaluation period (11.8 ± 0.6 g/dl in both), the mean required darbepoetin alpha dose decreased from 34.7 ± 2.1 to 26.0 ± 1.8 µg (–25%, P < 0.0001), yielding a mean final conversion ratio of 1:336. A dose decrease was observed in 56 patients, no dose change in 28 and an increase in 16 patients. Dose reduction strongly depended on baseline epoetin dose: no dose reduction was required for baseline epoetin doses <5000 U/week, whereas a 37% lower mean dose was necessary for baseline doses of 7000–10 000 U/week. The darbepoetin alpha dose reduction did not depend on the previous epoetin type (alpha or beta) or the previous epoetin administration route (i.v. vs s.c.).

Conclusions. The mean darbepoetin alpha dose needed to keep Hb stable in patients previously treated with epoetin is significantly lower than the equimolar dose. Although the equimolar 1:200 conversion ratio is appropriate for lower epoetin doses (<5000 IU/week), the darbepoetin dose for patients converting from ≥5000 IU of epoetin per week is more likely to follow a 1:250 to 1:350 conversion rule. If pricing is based on the 1:200 rule such as in Switzerland, this may translate into cost savings.

Keywords: anaemia; darbepoetin; end-stage renal disease; epoetin; haemoglobin



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Darbepoetin alpha is a glycoprotein that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin and epoetin (recombinant human erythropoietin). The serum half-life of erythropoetins may be determined by their sialic acid-containing carbohydrates [1]. Darbepoetin alpha has five N-linked carbohydrate chains, whereas both endogenous erythropoietin and epoetin have only three. Because of its increased carbohydrate content, darbepoetin alpha has a 3-fold longer serum half-life than epoetin both in experimental animals and in man [2]. This is likely to offer a clinical advantage over epoetin by allowing less frequent dosing in patients treated for anaemia. In contrast to epoetin, there is no difference between intravenous (i.v.) and subcutaneous (s.c.) dose requirements [3,4].

In patients treated for renal anaemia, darbepoetin alpha has been shown to more effectively increase haemoglobin than equimolar amounts of epoetin administered by the same route [3,5,7]. However, these studies evaluated the darbepoetin alpha dose necessary to maintain haemoglobin (Hb) within a certain range and allowed asymmetrical boundaries for Hb [6–8], i.e. the allowed range for Hb to increase was bigger than to decrease. These asymmetrical boundaries may have biased the results in favour of an Hb increase during darbepoetin alpha titration.

Since, therefore, the actual conversion ratio from epoetin to darbepoetin alpha was unknown, the present study was designed to evaluate the darbepoetin alpha dose adjustment that was required to maintain Hb within symmetrical boundaries (±1.0 g/dl) of baseline after equimolar (1:200) conversion from epoetin. In addition, the study was to evaluate the relative influence of the previous route of administration, the previous dose frequency and the previous dose of epoetin on the darbepoetin alpha dose requirements. In contrast to earlier studies [4,6,9], where patients had been switched to darbepoetin alpha using the same route of administration as the previous epoetin (s.c. {Rightarrow} s.c., i.v. {Rightarrow} i.v.), darbepoetin alpha was consistently administered via the intravenous route in the present study, since this is the preferred route in haemodialysis patients.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Patients
Clinically stable haemodialysis patients ≥18 years of age with anaemia of ESRD who were receiving haemodialysis for at least 6 months were eligible for participation, if they were on stable epoetin ({alpha} or ß) therapy and had stable Hb between (and including) 10.8 and 13.0 g/dl. ‘Stable epoetin therapy’ was defined as having ≤25% (up or down) changes of the weekly epoetin dose within the last 8 weeks prior to study. ‘Stable Hb’ was defined as having Hb changes of <1 g/dl (up or down) in the last 2 months prior to study. In addition, patients needed to have adequate iron stores (serum ferritin ≥100 µg/l and transferrin saturation ≥20%). The patients were enrolled in 17 dialysis centres in Switzerland.

We excluded patients with treatment of grand mal epilepsy within the past 6 months, severe congestive heart failure (NYHA Class III or IV), uncontrolled hypertension (defined as a pre-dialysis diastolic blood pressure ≥110 mmHg), clinical evidence of uncontrolled hyperparathyroidism, major surgery within 12 weeks before the study (not counting vascular access surgery), suspected for infection based on an increased CRP value or receiving antibiotic therapy, alanine transaminase (ALT) and aspartate transaminase (AST) greater than two times the upper limit of normal, previously diagnosed HIV, chronic hepatitis B or C infection, current evidence of malignancy (with the exception of cutaneous basal or squamous cell carcinoma), red blood cell (RBC) transfusions, active bleeding or androgen therapy within 12 weeks before study, systemic haematological disease, untreated vitamin B12 or folic acid deficiency as well as patients scheduled for a living donor kidney transplant.

Study drug
The only investigational agent in this study was darbepoetin alpha (Aranesp®, Amgen Inc.). It was provided as a clear colourless HAS-free, sterile protein solution in syringes pre-filled with doses of 10, 15, 20, 30, 40, 50, 60, 80, 100 and 150 µg. Darbepoetin alpha was administered during the dialysis session as i.v. bolus through the venous dialysis line.

Study design
The study was conducted as a multicentre, open-label and single-arm study. The aim of the study was to determine the maintenance dose of darbepoetin alpha which would allow to keep Hb stable after switching from a maintenance dose of epoetin.

After an initial 1-week screening period and a 1-week baseline period, eligible subjects were converted from s.c. or i.v. epoetin to i.v. darbepoetin alpha. The initial weekly dose of darbepoetin alpha was determined by the baseline weekly epoetin dose and was based on peptide mass equivalents, i.e. 200 IU of epoetin were considered equivalent to 1 µg of darbepoetin alpha (200:1 rule), as suggested by the Swiss prescribing information. The frequency of darbepoetin alpha administration depended on the frequency of baseline epoetin therapy. Subjects treated with epoetin two or three times per week received darbepoetin alpha once weekly, whereas subjects previously receiving epoetin in one weekly dose were given darbepoetin alpha once every other week. Between the initial conversion and the evaluation period, Hb was maintained within ±1.0 g/dl of each patient's individual baseline value by changing the darbepoetin alpha dose as described subsequently. The baseline Hb was defined as the mean of the last three regular Hb determinations prior to the study, taken at least 1 week apart.

Haemoglobin was measured every 2 weeks. Dose changes were permissible if either two Hb values exceeded the pre-specified boundaries or if it was foreseeable, based on three consecutive Hb values, that Hb would exceed a boundary within the next 2 weeks. If Hb decreased below the subject's baseline value by >1.0 g/dl, the dose of darbepoetin alpha was increased to the next higher level given by the available pre-filled syringes. Conversely, if Hb increased by >1.0 g/dl above the subject's baseline Hb, the dose was decreased to the next lower level. If in patients receiving darbepoetin alpha every 2 weeks, the Hb concentration did still not increase into the target range with the maximal darbepoetin alpha dose (150 µg every other week), the dosing frequency was increased to once weekly. Conversely, if, in patients receiving weekly darbepoetin alpha, Hb still did not decrease into the target range with the lowest dose (10 µg/week), the frequency was decreased to once every other week. If a subject had two consecutive Hb values ≥14.0 g/dl, darbepoetin alpha was withheld until Hb had decreased to ≤13.0 g/dl and was then re-initiated at the next lower dose. If, at any time during the study, the Hb concentration decreased below 9.8 g/dl despite increasing the darbepoetin alpha dose and/or schedule as prescribed earlier, appropriate investigations and actions were taken as clinically indicated. After a period of 20 weeks used for dose titration and stabilization of Hb, patients entered the evaluation period of 4 weeks (week 21–24) during which primary efficacy endpoints were assessed.

If serum ferritin levels decreased below 100 µg/l or transferrin saturation below 20%, supplemental i.v. iron was administered according to the policy of each centre.

Safety was assessed by monitoring adverse events, laboratory variables (ferritin, transferrin saturation, serum albumin, creatinine, urea, ALT, AST, vitamin B12, folate, CRP, WBC and platelet count), vital signs and antibody formation to darbepoetin or epoetin. A radioimmuno precipitation (RIP) assay was used to detect darbepoetin/epoetin antibodies at screening and end of the study. The antibody testing was performed at the laboratory of MDS Pharma Services Switzerland AG in Fehraltdorf.

Study endpoints
The primary endpoint of the study was the change of darbepoetin alpha dose between screening/baseline and the evaluation period (week 21–24) which was required to maintain Hb within symmetrical ±1.0 g/dl boundaries of the baseline value. Secondary endpoints included the change in darbepoetin alpha dosage in terms of the following factors: previous epoetin type, previous application mode, previous epoetin dose and previous epoetin dosing frequency. Furthermore, the change in mean Hb concentration and safety variables were evaluated.

The study protocol was approved by each participating hospital's Ethics Committee and conducted in accordance with the Declaration of Helsinki. Study procedures and data validity were monitored by an independent contract research organization (PFC Pharma Focus AG Switzerland). All patients gave written informed consent before any study-related procedures were performed.

Statistical analysis and sample size
A 10% mean dose change of darbepoetin alpha was considered the smallest relevant change to be detected [6]. When considering a mean dose of darbepoetin alpha of 25 µg at baseline, then with a change of 2.5 ± 7.5 µg [95% confidence interval (CI) 0.94–4.06], 90 evaluable patients and a two-tailed-{alpha} of 5%, the study would have a power of 88% to yield a statistically significant result. With 100 evaluable patients, the power would increase to 91%, and with 120 patients to 95%. Anticipating a 20% dropout rate, we therefore aimed at recruiting approximately 150 patients.

Comparisons between the evaluation and the screening/baseline periods were done using the paired t-test or the Wilcoxon signed rank test depending on the data distribution. A two-sided-{alpha} value of 0.05 was considered significant. The stability of factors relevant for the responsiveness to erythropoesis stimulating agents (ESA) such as ferritin, transferrin saturation, i.v. iron dose, Kt/V, urea reduction rate and C-reactive protein was assessed using one-way analysis of variance (ANOVA) followed by the post-hoc least-significant-difference (LSD-) test. Data are presented as means ± SD or SEM as appropriate.

The efficacy analysis included all patients who completed the 20-week titration period and entered the evaluation period. The safety analysis included all patients who had received at least one dose of darbepoetin alpha during the study. Since the main study endpoint was the change between the screening/baseline dose and the evaluation period dose, an intention-to-treat analysis was considered meaningless.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Appendix
 Acknowledgements
 References
 
Study demographics and baseline characteristics
Of 157 patients screened for the study, 25 did not fulfil one or more of the inclusion criteria and never received the study drug. All of the remaining 132 patients were converted from epoetin to darbepoetin alpha. Twenty-four of these (18%) did not complete the 24-week study period, because they died (n = 7), received a kidney transplant (n = 7), received RBC transfusions (n = 6), withdrew consent (n = 3) or because there was a protocol violation (untreated iron deficiency at baseline, n = 1). Protocol violations in eight additional patients (6%) were recognized after finishing the 24 weeks protocol, including evidence for baseline deficiency of iron (n = 2) or vitamin B12 (n = 2), erroneous administration of epoetin during the study (n =1), lack of a stable Hb baseline (n = 2) and adjustments of darbepoetin alpha dose not conforming to the protocol (n = 1). Most of these exclusions would have tended to increase the ‘dose savings effect’ of darbepoetin alpha if they had remained in the analysis. The remaining 100 patients (76%) were included in the efficacy analysis, whereas all 132 patients were included in the safety analysis (Figure 1). Demography and baseline characteristics of the 100 patients included in the efficacy analysis were similar to the larger group of 132 patients included in the safety analysis (Table 1).


Figure 1
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  		Fig. 1. Patient disposition.

 

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  		Table 1. Patient demography and baseline characteristics

 
At baseline, there were more patients receiving epoetin beta (71%) than alpha (29%). Consistent with European recommendations at the time of study, virtually all patients receiving epoetin alpha did so by the i.v. route (27 of 29), whereas the application route was predominantly s.c. in the epoetin beta patients (49 of 71 patients; P < 0.001). Overall, approximately half of all patients received epoetin by the i.v. and s.c. route (49 vs 51%). Forty-five percent of the patients received epoetin two or three times per week and hence received darbepoetin alpha once weekly; 55% received it every 2 weeks. Since the application of epoetin twice or three times weekly mainly occurred in patients with high dose requirements, the baseline epoetin dose was significantly lower in the patients receiving darbepoetin alpha every 2 weeks compared to the patients receiving it weekly (5164 IU ± 2559 vs 9111 IU ± 4787; P < 0.0001).

Factors relevant for ESA responsiveness
Serum ferritin was stable (ANOVA P = 0.53) in the high normal range with mean values (±SE) of 561 ± 52 ng/ml at baseline (week 0), 530 ± 53 in week 8, 572 ± 50 in week 16 and 636 ± 52 in week 24. The ANOVA for transferrin saturation was significant (P < 0.005) due to a decrease from week 0 (mean ± SE 36 ± 2%) to week 8 (32 ± 1%), week 16 (29 ± 1%) and week 24 (30 ± 1%). On post hoc analysis using the LSD test, only transferrin saturation in week 0 was significantly higher than in week 8, week 16 or week 24, whereas transferrin saturations in weeks 8, 16 and 24 did not differ significantly among each other.

Patients were well dialysed at baseline (mean Kt/V 1.66 ± 0.04; mean urea reduction rate 75 ± 0.6%). Urea reduction rate at the end of study was unchanged (75 ± 0.7%).

The weekly dose of i.v. iron did not change significantly throughout the study (P = 0.15) and was (mean ± SE) 25 ± 3 mg in weeks 1–4, 28 ± 3 in weeks 5–8, 35 ± 3 in weeks 7–12, 32 ± 3 in weeks 13–16, 33 ± 3 in weeks 17–20 and 31 ± 3 in weeks 21–24.

Mean CRP did not change between week 0 (7.5 ± 0.9 mg/l) and week 24 (9.3 ± 1.4 mg/l; P = 0.30). Dose savings (both absolute and relative) after switching from rHuEpo (see subsequently) did not correlate with baseline ferritin, baseline transferrin saturation or baseline CRP.

Efficacy of darbepoetin alpha
The mean Hb concentration at baseline was 11.8 ± 0.6 g/dl (n = 100), and there was no significant change from baseline to the evaluation period (Table 2). Hb was required to be stable by protocol (changes <1 g/dl in the preceding 2 months) and, in addition, showed no trend to decrease or increase in the weeks prior to the switch (Figure 2). The mean Hb values at baseline and during the evaluation phase were comparable irrespective of epoetin type, route of administration, weekly dose and baseline frequency of epoetin (Table 2). There was, however, a small increase in mean Hb during the first 6 weeks, which later reverted back almost to starting values, reflecting the delay in recognizing that, in many patients, the switch from epoetin to darbepoetin alpha according to the 1:200 rule led to a decreased dose requirement (Figure 2).


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  		Table 2. Mean Hb concentration at baseline and in the evaluation period by subgroups

 

Figure 2
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  		Fig. 2. Mean Hb concentration (±SD) during the study (n = 100). Weekly Hb data were obtained by linear interpolation.

 
The normalized variability of Hb during the titration phase (SD of bi-weekly Hb values divided by each patient's mean Hb) was similar in patients receiving darbepoetin alpha weekly and every other week (5.1 ± 2.7% and 4.3 ± 2.0%, respectively, P {approx} 0.09).

Darbepoetin alpha dose requirements
The mean weekly darbepoetin alpha dose during the evaluation period was 26.0 ± 1.8 µg (SEM). This was significantly lower than the mean weekly darbepoetin alpha dose of 34.7 ± 2.1 µg immediately after conversion (difference –8.7 µg (–25%); 95% CI –11.6 to –5.8 µg, P < 0.0001) and was the result of a continuous decrease of the administered darbepoetin alpha dose in the course of the study. It was most pronounced between the 5th and the 9th study week, but nevertheless persisted to the 20th week (Figure 3). A significant dose reduction was found in three subgroups that were pre-defined by previous epoetin type (alpha vs beta), epoetin application mode (i.v. vs s.c.) and darbepoetin alpha dosing frequency (1/week vs 2/week) (Table 3). When patients were stratified by previous epoetin weekly dose, significant dose reductions were only found for baseline weekly epoetin doses ≥5000 IU/week. In all but one of the study centres, the mean darbepoetin alpha dose per centre also decreased, whereby the reduction ranged from –2 to –65%.


Figure 3
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  		Fig. 3. Mean weekly darbepoetin alpha dose (±SEM) during the titration period.

 

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  		Table 3. Darbepoetin alpha dose reductions by subgroups

 
The potential for dose reduction after conversion to darbepoetin alpha depended on baseline weekly epoetin dose. In a stepwise linear regression model of dose saving ({triangleup}) of darbepoetin alpha vs baseline epoetin dose, type of administration (i.v. vs s.c.), type of epoetin (alpha vs beta) and the dosing frequency (1/week vs 1/2 weeks), only baseline weekly epoetin dose remained significant after elimination of all other variables ({triangleup} darbepoetin alpha = 3.28 – 0.0017 * epoetin units; r = 0.51, P < 0.0001, Figure 4).


Figure 4
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  		Fig. 4. Relation of darbepoetin alpha dose savings to baseline epoetin dose. Ordinate: weekly darbepoetin alpha dose in the evaluation phase minus the dose immediately after 1:200 conversion. Data have been jittered by the computer program to avoid overlaying of data points. Open circles: darbepoetin alpha 1/week; closed circles: darbepoetin alpha 1/2 weeks. The linear regression equation was: {triangleup} darbepoetin alpha = 3.28 – 0.0017 * epoetin units (r = 0.51, P < 0.0001). Continuous line: regression line; dashed line: 95% confidence intervals for the mean.

 
The direction of dose changes during the 20 weeks of the titration phase was also evaluated. A decrease of the weekly dose was observed for 56 patients (in one of these, darbepoetin alpha was stopped in week 20), no dose change in 28 and an increase in 16 patients. Dose changes during the 20 weeks of the titration phase tended to be more common in patients receiving darbepoetin alpha every week than in patients receiving it every other week [2.3 ± 2.1 vs 1.6 ± 1.6 changes per patient, P {approx} 0.06 (Mann–Whitney U-test)]. A similar, statistically significant trend was observed if only the second half of the titration phase (days 74 through 147) was considered, when presumably most of the dose adjustment resulting from the epoetin-to-darbepoetin switch had already taken place (1.5 ± 1.4 vs 1.0 ± 1.3 changes per patient; P < 0.05).

Conversion ratio
The final mean conversion ratio from epoetin to darbepoetin alpha was 336:1 (95% CI: 284–388). The type and administration route of baseline epoetin had no significant influence on the mean conversion ratio, but it was positively correlated with baseline epoetin dose (Figure 5).


Figure 5
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  		Fig. 5. Conversion factors vs baseline weekly epoetin dose for all 100 patients. The ordinate shows the ratio of baseline weekly epoetin dose (IU) to weekly darbepoetin alpha dose (µg) in the evaluation phase. The regression equation was: conversion factor = 224.8 e(Epoetin dose x 0.0000314) (r = 0.24, P < 0.02).

 
Safety of darbepoetin alpha
Overall, 169 adverse events were reported in 76 of the 132 study patients who had received darbepoetin alpha at least once, 34 of which were serious, including seven deaths. None of the serious adverse events was considered related to darbepoetin alpha administration by the investigators. The deaths in two cases followed trauma (fall on the back and hip fracture) or resulted from myocardial infarction, circulatory collapse, suspected aneurysm bleeding, stage IV peripheral arterial occlusive disease and Staphylococcus aureus sepsis (n = 1 for each). The most common groups of serious adverse events were circulatory (n = 8), gastrointestinal (n = 6) and infections (n = 6).

The most common adverse events were: infections (n = 22, mostly minor), shunt stenosis (n = 15) and hypertension (n = 11). Fifteen adverse events were reported as possibly related to the darbepoetin alpha treatment. These included: hypertension (n = 9), dizziness, peripheral artery occlusive disease, fever, sweating, shivering and shunt stenosis (n = 1 for each).

No significant changes from screening/baseline values were observed in clinical laboratory tests including serum albumin, urea, ALT/AST, CRP, vitamin B12, folate, WBC and platelets. In one patient, antibodies against epoetin or darbepoetin alpha were detected at screening and week 24. Since further analysis in the laboratory of Professor Nicole Casadevall, Paris, France showed that the antibodies were not neutralizing, this patient was kept in the study.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Appendix
 Acknowledgements
 References
 
This is the first prospective study that was explicitly designed to investigate the conversion ratio from epoetin to darbepoetin alpha. While most previous conversion studies were designed to merely show that darbepoetin alpha was able to maintain Hb after conversion [4,6,7,9], the present study attempted to find the darbepoetin alpha dose that would maintain Hb stable, i.e. within a ±1.0 g/dl window of each individual's baseline Hb. Based on both compounds’ protein content, the correct ratio was originally assumed to be 1 µg of darbepoetin alpha or beta for every 200 units of epoetin alpha or beta.

In order to find the equivalence dose, it was paramount that participants entering this study were optimally stable and treated with sufficient amounts of iron, vitamin B12 and folic acid, wherever needed. The inclusion criterion of having a stable Hb, i.e. changes of no more than 1.0 g/dl within the preceding two months, and stable epoetin dose, i.e. ≤25% change in the preceding 8 weeks, represent commonly accepted clinical criteria for Hb stability. In addition, there was no trend for mean Hb to increase or decrease prior to the switch (Figure 2). Hb was measured every 2 weeks and doses of darbepoetin alpha were adapted according to a pre-specified algorithm. Finally, there were no changes in ferritin, intravenous iron dose or CRP throughout the study and only a minor decrease of transferrin saturation from week 0 to week 8. The latter might be actually considered to be a consequence of the increased erythropoesis which ensued after conversion before all patients were down-titrated to the correct maintenance dose (Figure 2).

The baseline stability of this study's patients is supported by the fact that mean Hb was stable prior to conversion and remained so for ~4 weeks after conversion. Only thereafter was there a clear Hb increase (Figure 2), which prompted a sustained decrease of the darbepoetin alpha dose from the 1:200 conversion dose (Figure 3).

This dose decrease was, however, not uniform but depended on the baseline epoetin dose. While there was virtually no deviation from the 1:200 conversion if baseline weekly epoetin dose was below 5000 units (Table 3), dose savings amounted to 30–35% with baseline doses of 10 000 units and more. There was a highly significant negative linear correlation between baseline epoetin dose and dose savings after conversion to darbepoetin alpha (Figure 4). The exponential regression of the final conversion factor to baseline epoetin dose indicated that the conversion factor increased from 200 (at weekly epoetin doses of 1000–2000) to more than 300 at doses >10 000 units (Figure 5). This increase in conversion ratio has been observed in earlier post hoc analyses of studies not designed to answer this question [9,10], although other authors have observed no such dependence [11] or even concluded that a conversion ratio of less than 200 was appropriate [12]. The present study provides evidence for the curvilinear relation between baseline epoetin dose and the conversion factor.

In theory, these data may be either interpreted as darbepoetin alpha at higher doses being more effective than epoetin or—more likely—as epoetin (but not darbepoetin alpha) losing efficacy at higher doses as first suggested by Nissenson [10].

If the overall conversion effect is considered, there was a 25% dose savings effect relative to the 1:200 rule in this population of Swiss dialysis patients with a mean weekly dose of approximately 7000 units of epoetin. This is consistent with the data by Tolman et al. [13] who found a 20% dose decrease when converting from epoetin beta to darbepoetin alpha according to the 1:200 rule. The present data also concur with the findings by Roger who reported a 1:275 conversion rate [11], and with the regulations of the U.S. Medicare and Medicaid Services who decided to consider 260 IU of epoetin as equivalent to 1 µg of darbepoetin alpha [14].

This dose savings effect was clearly not dependent on the type of epoetin previously given (alpha or beta; Table 3). When comparing patients previously given s.c. vs i.v. epoetin, the savings effect was more pronounced in patients previously given i.v. epoetin (–28 vs –23% with s.c. application of epoetin). This of course is consistent with the notion that epoetin is 20–30% more efficient when administered via the s.c. route.

That the dose savings effect was larger in patients receiving darbepoetin alpha once weekly than in patients receiving it every 2 weeks can not be taken to indicate lesser efficacy of every 2 weeks administered darbepoetin alpha. In contrast, this effect is entirely attributable to the fact that patients converted to weekly darbepoetin alpha had much higher (almost twice as high, see Table 3) baseline epoetin/darbepoetin requirements than patients converted to fortnightly darbepoetin alpha. By protocol, only patients receiving 2 or 3 weekly doses of epoetin were put on weekly darbepoetin alpha. This preferentially selected patients with higher weekly epoetin doses into the group that were given weekly darbepoetin alpha. Figure 4 shows that patients on fortnightly darbepoetin alpha blended into the same regression cluster as patients on weekly darbepoetin alpha.

Since in the EU and Switzerland, the pricing of epoetin and darbepoetin alpha is based on the protein content, i.e. the 1:200 rule, economically relevant cost savings may result if patients are converted from epoetin to darbepoetin alpha. The present study, however, indicates that such savings may only be expected with baseline weekly epoetin doses ≥5000 units.

In summary, the mean darbepoetin alpha dose needed to keep Hb stable in patients previously treated with epoetin is significantly lower than the equimolar dose. Although the equimolar 1:200 conversion ratio is appropriate for lower epoetin doses (<5000 IU/week), the darbepoetin dose for patients converting from ≥5000 IU of epoetin per week is more likely to follow a 1:250 to 1:350 conversion rule. If pricing is based on the 1:200 rule such as in Switzerland, this may translate into relevant cost savings.



   Appendix
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
Acknowledgements
 References
 
Efixnes trial investigators
H. Andreas Bock (Kantonsspital Aarau), Patricia Hirt (Regionalspital Emmental Burgdorf), Michel Brünisholz (Hôpital régional Porrentruy), Gerald Keusch (Waidspital Zürich), Beat von Albertini (Clinique Cécil Lausanne), Denes Kiss (Kantonsspital Liestal), Rudolf Wüthrich (Kantonsspital St. Gallen), Zeev Glück (Regionalspital Biel), Andreas Fischer (Kantonsspital Luzern), Hans Rudolf Räz (Kantonsspital Baden), Patrice Ambühl (Universitätsspital Zürich), Dominik Uehlinger (Inselspital Bern), Michel Burnier (CHUV Lausanne), Hermann Saxenhofer (Lindenhofspital Bern), Michael Dickenmann (Kantonsspital Basel), Pierre Yves Martin (HUG Geneve) and Heinrich Heule (Dialysepraxis Altstätten)



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 Acknowledgements
References
 
This was an investigator-initiated study supported by a grant from Amgen Inc. We thank all participating investigators, Martin Gerber for statistical advice and data analysis and PFC Pharma Focus AG Switzerland for study coordination.

Parts of this study were presented at the 2004 meeting of the American Society of Nephrology, at the 2004 Meeting of the Gesellschaft für Nephrologie and at the 2005 EDTA-ERA congress.

Conflict of interest statement. None declared.



   Notes
 
*The investigators are listed in the Appendix. Back



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 

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Received for publication: 13.12.06
Accepted in revised form: 30. 7.07


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