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Nephrology Dialysis Transplantation 2007 22(Supplement 4):iv19-iv30; doi:10.1093/ndt/gfm162
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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

Extended dosing intervals with erythropoiesis-stimulating agents in chronic kidney disease: a review of clinical data

Fernando Carrera1, Alex Disney2 and Manuel Molina3

1Eurodial, Dialysis Unit, Leiria Portugal, 2Queen Elizabeth Hospital, Adelaide, South Australia and 3Servicio de Nefrologia, Hospital Santa Maria del Rosell, Cartagena, Spain

Correspondence and offprint requests to: Fernando Carrera, MD, Eurodial, Dialysis Unit, Rua da Carrasqueira 19, Parceiros, 2400-441, Leiria, Portugal. Email: fcarrera{at}mail.telepac.pt



   Abstract
Top
 Abstract
Introduction
 Clinical trials
 Tolerability
 Pharmacoeconomic studies
 Discussion
 References
 
The recombinant human erythropoietins epoetins alfa and beta have relatively short half-lives (~24 h by subcutaneous route) and have traditionally been administered 2 or 3 times a week for the treatment of anaemia in patients with chronic kidney disease. However, multiple weekly injections are inconvenient for both the patient and the healthcare provider. With the introduction of the longer-acting erythropoiesis-stimulating agent darbepoetin alfa, there has been growing interest in longer dosing intervals for erythropoiesis-stimulating agents. Data from several randomized studies have shown that darbepoetin alfa is effective in maintaining haemoglobin levels when administered (subcutaneously, intravenously or both) every 2 weeks in dialysis patients, and every 2 weeks or monthly in patients with chronic kidney disease not yet receiving dialysis. Moreover, intravenous administration with darbepoetin alfa does not require a higher dosage compared with the subcutaneous route. Epoetins alfa and beta have also been studied in similar schedules, although few data from well-designed studies are available. Current data suggest that once-weekly administration of these forms of epoetin is feasible in dialysis patients, but dose increases are often required when switching patients from traditional twice- or thrice-weekly schedules. Also, administration of epoetins every other week is feasible in selected patients with chronic renal insufficiency. Further study is required to clarify the optimum schedule for epoetins in these settings.

Keywords: anaemia; chronic kidney disease; darbepoetin alfa; dosing schedule; erythropoiesis-stimulating agents; extended dosing intervals



   Introduction
Top
 Abstract
 Introduction
Clinical trials
 Tolerability
 Pharmacoeconomic studies
 Discussion
 References
 
Renal anaemia, resulting from decreased production of erythropoietin by the kidney, can develop in the early stages of chronic kidney disease (CKD) and is present in virtually all patients who require dialysis. Anaemia is associated with serious and often irreversible complications, including cardiac disease, and has been shown to increase the risk of mortality. Correction of anaemia in patients with CKD prolongs survival, reduces morbidity and improves clinical outcomes [1]. Accordingly, the European Best Practice Guidelines (EBPGs) for the Management of Anaemia in Patients With Chronic Kidney Disease [2] recommend a target haemoglobin (Hb) level >11 g/dl in this population (some modifications are recommended for those with significant risk from cardiac or peripheral vascular disease).

Recombinant human erythropoietins (rHuEPOs) such as epoetin alfa and epoetin beta have proven efficacy in treating anaemia in CKD patients [1,2]. Because of their relatively short half-lives (~24 h when administered via the subcutaneous [SC] route) [3], these agents are usually administered two or three times a week (BIW/TIW). However, multiple weekly injections are inconvenient for patients and healthcare providers, particularly in the setting of chronic disease.

Darbepoetin alfa is a longer-acting erythropoiesis-stimulating agent (ESA) that contains two additional N-linked sialic acid-containing carbohydrate chains compared with endogenous erythropoietin and the standard rHuEPO molecules [4–6]. Its serum half-life is markedly longer than that of the rHuEPOs, and it also has greater erythropoietic activity [3,4,7,8]. Recent studies have shown that the mean terminal half-life of darbepoetin alfa approximates 73 h following SC administration in peritoneal dialysis (PD) patients and patients with CKD not yet receiving dialysis [i.e. patients with chronic renal insufficiency (CRI), CKD stage 3 or 4] [8–10]. (A more detailed review of the pharmacokinetics and pharmacodynamics of darbepoetin alfa is provided by Macdougall et al. in this issue.) Thus, darbepoetin alfa may be administered less frequently than standard rHuEPOs and still maintain adequate serum concentrations to stimulate erythropoiesis and maintain target Hb levels [7,11].

Since the introduction of darbepoetin alfa, there has been a general shift towards less frequent dosing regimens with ESAs, as reflected in the revised EBPGs [2]. This review examines clinical data on extended dosing intervals with available ESAs for the management of renal anaemia in patients with CKD.



   Clinical trials
Top
 Abstract
 Introduction
 Clinical trials
Tolerability
 Pharmacoeconomic studies
 Discussion
 References
 
Extended-interval ESA dosing regimens have been studied in patients on dialysis (haemodialysis and PD) and in those with CRI (Tables 1–3GoGo). Several studies switched patients with stable Hb levels from rHuEPO therapy [BIW/TIW or once weekly (QW)] to an extended dosing regimen [QW, once every 2 weeks (Q2W), or once monthly (QM)] with darbepoetin alfa or rHuEPO [12–25]. In several randomized, prospective studies, patients were assigned either to continue with their existing ESA regimen or to convert to a less-frequent dosing regimen with the same or a different agent [18–20,25]. In the CRI setting, a number of studies evaluated extended dosing regimens in patients who had not previously received ESA therapy [26–31].


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  		Table 1. Less-frequent ESA administration in dialysis patients

 

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  		Table 2. Less-frequent ESA administration in peritoneal dialysis patients

 

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  		Table 3. Less-frequent ESA administration in patients with CRI (CKD stages 3–4; not receiving dialysis)

 
When converting an individual already receiving ESA treatment (BIW, TIW or QW) to an extended dosing regimen (QW, Q2W or QM), the dose was increased proportionately to cover the increased interval. For example, patients switched from a BIW to a QW epoetin schedule received twice their previous dose in a single weekly injection. For converting patients from rHuEPOs to darbepoetin alfa, European studies used an initial dose conversion factor based on equivalent peptide mass: 200 units (U) of rHuEPO to 1 µg of darbepoetin alfa [32]. For studies conducted in the USA, patients were converted from rHuEPO to darbepoetin alfa using the dose conversion recommended in the USA Aranesp® label [27,33,34]. This system uses rounded doses of darbepoetin alfa: for example, a weekly darbepoetin alfa dosage of 25 µg is recommended for patients previously receiving rHuEPO doses between 5000 and 10 999 units/week. Uniform ESA doses were also studied in ESA-naïve patients [35].

Dosage was subsequently adjusted during a predefined titration period in most studies to achieve or maintain the Hb target. One study employed a computerized decision-support system for treatment interventions in order to maintain Hb within a narrow range [21]. Previous routes of administration were usually maintained [12,14–25,36–38], although switching from the SC to the intravenous (IV) route, or vice-versa, was also studied in dialysis patients [13,39–41]. In order to ensure an adequate level of iron to support the erythropoietic response, IV or oral iron supplementation was given in some studies.

A large number of patients discontinued study treatment, particularly in the longer-duration studies (Tables 1–3GoGo). Discontinuations generally were for reasons expected in this highly morbid patient population and included renal transplant or death, and in CRI patients, initiation of dialysis.

Haemodialysis patients
Darbepoetin alfa
The IV route is preferred for patients receiving haemodialysis, as the existing vascular (venous) access can conveniently be utilized. According to the Dialysis Outcomes and Practice Patterns Study (DOPPS), in 2003 the IV route was the principal route of rHuEPO administration to patients receiving haemodialysis in 11 of the 12 countries in which the study was conducted [42]. With rHuEPOs, a higher dose (up to 32%) may be needed for IV administration compared with the SC route [43], although a need for increased dosing was not identified in all studies [44]. The dosages of darbepoetin alfa by the IV and SC routes are usually reported to be equivalent [15,16,25,40], with data from a recent crossover study in dialysis patients (n = 58) even suggesting that the IV route might allow stable Hb levels to be maintained with a lower dose [40].

Several studies have demonstrated that patients on dialysis who are receiving rHuEPOs can be switched to QW or Q2W IV or SC darbepoetin alfa without an increase in their weekly dosage (Table 1). For most studies, patients who were previously receiving BIW/TIW rHuEPO were switched to QW darbepoetin alfa, while those already receiving QW rHuEPO treatment were switched to Q2W darbepoetin alfa [13,15–18,21,25]. Patients also can be switched from BIW/TIW rHuEPO directly to Q2W darbepoetin alfa [14]. Haemoglobin levels were successfully maintained in all studies (Table 1), and in those studies that provided such information, at least 95% of patients maintained these less-frequent darbepoetin alfa dosing regimens during the evaluation period [15–17,25].

A large subgroup analysis of data from eight 24-week European studies evaluated switching haemodialysis or PD patients (n = 1101) from IV or SC QW rHuEPO to Q2W darbepoetin alfa administered by the same route [17]. Eighty-five percent of patients with evaluable Hb values (n = 979) maintained target Hb levels of 10.0 to 13.0 g/dl with Q2W darbepoetin alfa, and 97% of patients were able to remain on the Q2W dosing schedule. The slight decrease in mean Hb from baseline (–0.27 g/dl; 95% CI, –0.34 to –0.20 g/dl) was not considered clinically relevant, and the mean darbepoetin alfa dose was similar at evaluation compared with baseline (0.22 vs 0.21 µg/kg/week).

The non-inferiority of the Q2W IV darbepoetin alfa regimen to the QW IV darbepoetin alfa regimen was confirmed in a randomized, double-blind study in 308 patients with baseline Hb 10.0 to 13.0 g/dl switched from TIW, BIW or QW IV rHuEPO regimens [14]. For the primary analysis set (n = 213), the lower limit of the 95% CI for the difference in mean change in Hb between the QW and Q2W darbepoetin alfa groups at evaluation was above the –0.5 g/dl threshold (difference = –0.23 g/dl [95% CI: –0.49, 0.04 g/dl]), thereby meeting the predefined endpoint for non-inferiority of the Q2W schedule. Additionally, Carrera et al. [45] demonstrated that patients who were receiving QW darbepoetin alfa (n = 105) could be switched to Q2W darbepoetin alfa without decrease in Hb levels or an equivalent weekly dose increase. The mean Hb levels did not change when comparing the first 6 months on the QW regimen to that of the subsequent 6 months on the Q2W regimen (11.7 ± 0.8 g/dl vs 11.7 ± 1.0 g/dl; P = 0.8). Corresponding weekly darbepoetin alfa dosages were 34.0 and 32.1 µg, respectively.

Recombinant HuEPOs (epoetin alfa and epoetin beta)
Once-weekly epoetin alfa or epoetin beta administration has been evaluated in dialysis patients previously receiving these agents in traditional BIW/TIW regimens. The SC route was most commonly used (Table 1) [12,19,20]. Switching to QW dosing frequently led to a slight decrease in mean Hb levels and/or an increase in rHuEPO dosage [12,19]. For instance, in one study (n = 358) the mean weekly dose of epoetin alfa increased from 85.1 to 92.1 IU/kg (P < 0.05) after switching. Sixty-nine percent of patients maintained target Hb levels [12]. Similar outcomes were seen in an audit of previously stable patients (n = 36) who were switched to QW epoetin alfa or beta. The Hb achieved by >85% of patients fell from >11.0 to >9.5 g/dl, and the mean rHuEPO dose increased from 97 to 107 IU/kg/week [46].

Two randomized studies compared QW and BIW/TIW regimens of SC epoetin beta (Table 1) [19,20]. Both groups of investigators concluded that the standard and less-frequent regimens were equivalent, despite the less than optimal comparison methodologies (e.g. inadequate power calculations for a non-inferiority study design). Also, the high number of patients (25%) withdrawn from one study [19] before evaluation, which exceeded the proportional difference used for sample-size calculation (20%), has been highlighted [47]. In the other study, the between-group difference in time-adjusted haematocrit (Hct) AUC was –0.56 (90% CI: –1.22 to 0.11) and –0.54 (–1.27 to 0.19) percent volume for the intent-to-treat and per-protocol populations, respectively. Mean and median Hct values and the proportion of patients within target were not stated. The rHuEPO dose increased by a median of 1.0 IU/kg/week in the QW group. The investigators commented that the rHuEPO dose increases that occurred towards the end of the 24-week study could be attributed to a relatively small proportion of patients [20].

Comparison of ESAs
Two large, randomized, comparative studies demonstrated that darbepoetin alfa administered at QW or Q2W dosing intervals was at least as effective in maintaining Hb levels as more frequent treatment (BIW/TIW) with rHuEPO (epoetin alfa or beta) over a period of 28 weeks [18] or 1 year [25]. These studies were specifically designed to demonstrate non-inferiority [18,25]. Analysis confirmed that the reduced frequency of dosing did not increase the proportion of patients with unstable Hb [18,25], although it should be noted that both studies used a very wide target Hb range (9–13 g/dl).

Molina et al. [41] compared the effects on ESA dosage requirements of changing the epoetin alfa administration route from SC to IV or switching to QW darbepoetin alfa IV or SC in haemodialysis patients previously receiving a stable dose of epoetin alfa QW or BIW SC for the previous 8 weeks. The total weekly epoetin alfa dose requirements for maintaining the Hb in the target range of 11 to 13 g/dl increased significantly (+39%; P < 0.001) upon changing from SC to IV rHuEPO administration (BIW or TIW). For those patients switched from epoetin alfa SC or IV (frequency not specified) to darbepoetin alfa SC or IV QW, the ESA dose requirement actually decreased, with the QW darbepoetin alfa dose being 0.903 µg/kg at baseline and 0.676 µg/kg at evaluation after 24 weeks (P < 0.001).

Additionally, Carrera et al. found that QW IV darbepoetin alfa was as effective in maintaining Hb levels as TIW IV rHuEPO. Patients receiving haemodialysis were stabilized on epoetin alfa IV TIW (target Hb: 11.0–12.5 g/dl) for 6 months, then randomized to continue this regimen or switch to darbepoetin alfa IV QW for 10 months. Mean Hb increased by 0.12 g/dl in the darbepoetin group and by 0.05 g/dl in the rHuEPO group. There was a significant difference (P = 0.03) between the two treatment groups in the mean change in weekly dosage (increase in rHuEPO dose and decrease in darbepoetin alfa dose from baseline) [48].

Recently, QW SC epoetin beta was compared with QW SC darbepoetin alfa in a 9-month study in 217 unselected patients previously receiving BIW/TIW epoetin beta (Table 1) [21]. In this randomized study, a computerized decision-support system was used for dose adjustments, allowing direct comparison of ESA doses required to maintain comparable Hb levels while simultaneously avoiding bias. When final doses of ESAs were compared using the European conversion formula (200:1), the mean weekly epoetin beta dose was found to be 44% higher than the darbepoetin alfa dose (133 vs 92 IU/kg; P = 0.001; Figure 1). As acknowledged by the authors, the design of the study would have been improved by the inclusion of a concurrent TIW epoetin beta arm, but the data are nevertheless of interest.


Figure 1
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  		Fig. 1. Comparison of weekly EPO beta (n = 81) and darbepoetin alfa (n = 81) in haemodialysis patients previously receiving SC TIW EPO beta: mean Hb and weekly dose over 9 months [21] (permission granted to reproduce).

 
Peritoneal dialysis patients
Although several of the studies in Table 1 included both haemodialysis and PD patients [15–17,25], few have specifically examined extended dosing intervals in PD patients (Table 2).

Darbepoetin alfa
Data from a pooled subanalysis of eight trials [23] and a small open-label, prospective study [22] (n = 17 patients) indicate that PD patients can be switched from BIW, TIW, or QW SC epoetin alfa treatment to a QW or Q2W SC darbepoetin alfa regimen without a weekly dose increase. Mean Hb levels remained stable throughout treatment and mean darbepoetin alfa dosage was 0.35 and 0.30 µg/kg/week for QW and 0.20 and 0.19 µg/kg/week for Q2W treatment at baseline and evaluation, respectively [23]. Almost all patients (96 to 100%) were able to maintain these less-frequent dosing schedules [22,23], and more than 80% remained within the target Hb range (Table 2).

Epoetin beta
Grzeszczak et al. [24] evaluated switching 190 PD patients receiving SC epoetin beta to a QW (those previously receiving BIW/TIW treatment) or Q2W (those previously receiving QW treatment) regimen. Mean Hb levels remained within the specified target range of 10.0 to 12.0 g/dl, with a slight decrease from baseline in both treatment arms. Mean weekly rHuEPO dosage increased slightly (13%) in the Q2W group compared with the dosage in the QW group (Table 2).

Patients with CRI (CKD stage 3 or 4)
Table 3 summarizes data from several studies that assessed less-frequent dosing schedules with ESAs, using the SC route, in patients with CRI.

Darbepoetin alfa
Q2W regimen
Several studies have demonstrated that Q2W darbepoetin alfa is effective for achieving Hb targets in ESA-naïve patients with CRI [27,29–31] and maintaining Hb levels in CRI patients already receiving ESA treatment [33,36–38, 49].

For instance, two prospective studies evaluated Q2W darbepoetin alfa in ESA-naïve patients with CRI and baseline Hb < 11 g/dl (n = 608 and n = 76, respectively) [30,31]. Almost all patients completing these studies (96 and 97%, respectively) achieved the target Hb level (11 to 13 g/dl), in a mean time of approximately 5 to 6 weeks [30,31]. In patients who were previously receiving QW epoetin alfa, Hb levels increased after switching to Q2W darbepoetin alfa, from 11.15 g/dl at baseline to 11.98 g/dl at 24 weeks (P < 0.001). Corresponding darbepoetin alfa dosages at these timepoints were 0.192 and 0.163 µg/kg Q2W [49].

The long-term efficacy of Q2W darbepoetin alfa in CRI patients was demonstrated in a 52-week study in both ESA-naïve patients [27] and those previously receiving QW epoetin alfa [33]. The latter group was converted to Q2W darbepoetin alfa using the conversion table in the USA Aranesp® package insert [34]. Mean (SD) Hb in these patients (n = 232) increased slightly from 11.2 (1.3) g/dl at baseline to 11.6 (1.1) g/dl at week 52. Corresponding Q2W mean (SD) dosages of darbepoetin alfa were 49.7 (21.9) and 51.8 (50.1) µg, respectively [33].

QM regimen
A QM regimen of darbepoetin alfa was effective in maintaining Hb levels in CRI patients who were previously stable on Q2W darbepoetin alfa (Table 3) [36–38]. Mean Hb levels were similar at baseline and evaluation in all studies and Hb targets were successfully maintained in at least 85% of patients. Mean dosage increased slightly in one study, from 80.0 to 83.9 µg/month [36].

Epoetin alfa
Once-weekly epoetin alfa was effective in increasing Hb levels in patients with CRI not previously receiving ESAs (Table 3). Mean Hb increased from ~9 to >10 g/dl [26,28,50]. For instance, in one 24-week study in which mean baseline Hb was only 8.8 g/dl, 17 of 19 patients (89%) who completed the study achieved the Hb target of 10 to 12 g/dl [50].

Switching CRI patients already receiving epoetin alfa therapy to various less-frequent dosing regimens—epoetin alfa QW (10 000 U), Q2W (20 000 U), once every 3 weeks (Q3W; 30 000 U) or QM (40 000 U)—has also been evaluated in 519 patients with stable Hb levels [35]. Dose reductions, but not increases, were allowed in this study. The Q2W and QM dosing regimens, but not the Q3W regimen, were reported to be non-inferior to the QW regimen with respect to final mean Hb values. The proportions of patients maintaining Hb ≥ 11 g/dl were 94 and 90%, respectively, in the QW and Q2W groups, but somewhat lower in the Q3W and QM treatment groups (77 and 76%, respectively). As acknowledged by the investigators, a longer follow-up duration than 16 weeks might have shown further differences between treatments, particularly as the average red blood cell (RBC) lifespan is around 120 days. It should also be noted that the epoetin alfa doses used in this study are very high compared to those generally used in Europe [51]. Moreover, as the frequency of the previous epoetin alfa regimen was not stated, it is not possible to judge whether the anaemia treatment received prior to study initiation was the typical treatment for CRI patients. In addition, 106 patients did not complete the study: treatment failure was the reason for discontinuation in 41 cases (ranging from 5.4% of the QW group to 12% of the QM group) [35].

Comparison of ESAs
A retrospective analysis (n = 94 patients) compared darbepoetin alfa and epoetin alfa both at Q2W or QM dosing intervals as de novo therapy: darbepoetin alfa 60 µg or EPO alfa 20 000 IU Q2W; darbepoetin alfa 100 µg or EPO alfa 40 000 IU QM [29]. The Hb response (estimated using a quadratic regression model based on the dosing regimens) to darbepoetin alfa was faster and of larger magnitude than the response to epoetin alfa. Haemoglobin response rates for both darbepoetin alfa regimens were similar, but with epoetin alfa the QM regimen was slower in increasing Hb levels than the Q2W regimen. The proportion of patients within target Hb ≥ 11 g/dl at evaluation did not differ significantly between the Q2W darbepoetin alfa and Q2W epoetin alfa groups (67 vs 54%). However, a significantly higher proportion of the QM darbepoetin alfa group achieved this target compared with the QM epoetin alfa group (80 vs 50%). Even at day 60, darbepoetin alfa dosing remained superior to rHuEPO dosing in achieving and maintaining target Hb levels (darbepoetin alfa 60 µg and 100 µg: Hb = 11.2 g/dl; epoetin alfa 20 000 IU: Hb = 11.0 g/dl; epoetin alfa 40 000 IU: Hb = 10.6 g/dl). It could be argued that the doses of epoetin alfa used in this study were much higher than the equivalent doses of darbepoetin alfa.



   Tolerability
Top
 Abstract
 Introduction
 Clinical trials
 Tolerability
Pharmacoeconomic studies
 Discussion
 References
 
Extended dosing regimens with ESAs are generally well tolerated. The type and incidence of adverse events experienced by patients receiving QW, Q2W and QM regimens of ESAs are similar to those associated with more frequent dosing regimens. Adverse events possibly related to ESA treatment included hypertension, injection site pain (SC administration), fatigue and vascular access thrombosis [15,16,18,21,22,24,25,28,30,31,37,50].

As extended ESA dosing intervals involve larger doses compared with traditional BIW/TIW regimens, concerns have been expressed regarding the risk of Hb overshoot and large fluctuations in Hb levels [52]. Recently, Singh and colleagues suggested a possible link between high ESA dosing, low haemoglobin levels, and mortality. In this study, patients with CRI were randomized to treatment with an ESA to achieve a Hb target of 13.5 or 11.3 g/dl [53]. The patients in high Hb target group were at greater risk of experiencing a primary composite outcome (death, myocardial infarction, hospitalization for congestive heart failure and stroke) compared with the low Hb target group. The investigators noted that over the course of the study the mean ESA dose was significantly greater in the high-target group compared with the low-target group, which suggests a possible association between high ESA doses and poor outcomes. There are several limitations to such an interpretation as this study was not designed to assess the relationship between ESA dose and clinical outcomes [54]. Further analyses are needed to elucidate the relationship between clinical outcomes, Hb levels and ESA dosing. Nevertheless, it is important that Hb monitoring requirements [2] are not overlooked during less-frequent dosing with ESAs. Generally, high Hb levels are not advisable in patients with CKD.

Hypertension is an additional concern in patients with CKD, many of whom receive antihypertensive therapy; blood pressure must be monitored closely during ESA treatment, particularly at the start of therapy [2]. Although extended dosing involves higher initial ESA doses compared with more frequent administration, most investigators reported that mean blood pressure remained stable and/or that there was no requirement for an increase in antihypertensive treatment throughout extended-interval ESA treatment [15,16,18,19,25,28,37]. In comparative studies, less frequent and traditional ESA regimens were associated with similar incidences of hypertension in dialysis patients [18,20,25]. While one study found a higher rate of hypertension with QW darbepoetin alfa than BIW rHuEPO (32 vs 22%, respectively), as acknowledged by the investigators, patients randomized to darbepoetin alfa had a greater burden of comorbidity at baseline, including a higher incidence of hypertension [5].

There were no clinically significant treatment-related changes in clinical or laboratory parameters in extended-dosing studies [15,16,18,20,22,24,25,31,50].



   Pharmacoeconomic studies
Top
 Abstract
 Introduction
 Clinical trials
 Tolerability
 Pharmacoeconomic studies
Discussion
 References
 
The potential benefits of less-frequent dosing with ESAs extend to patients, healthcare providers and payors.

For patients with CRI, less-frequent administration may offer greater comfort and convenience [55]. For those patients who receive their injections at the doctor's office or clinic, fewer injections could also translate into reduced visits and transportation costs. These benefits may potentially lead to improved compliance and outcomes [56]. Recently it was demonstrated that 88% of 346 CRI patients switched from QW or Q2W epoetin alfa to QM darbepoetin alfa and preferred the QM regimen [57]. The trend towards less-frequent ESA dosing is illustrated by data from an observational study that analysed the change in the proportion of CRI patients receiving QM darbepoetin alfa after nephrologists were informed of the possibility of using this dosage schedule [58]. Whereas only 2 (1.2%) of the 161 patients enrolled were receiving QM dosing initially, 71 (66%) of the 108 patients who completed the study were receiving QM dosing after 12 months. Fifty-nine percent of the evaluable patients said they preferred the QM dosing regimen.

In the haemodialysis setting, less-frequent ESA administration might result in decreased in-centre nursing time and potentially reduce costs. For example, it was estimated that 388 of 577 total hours of nursing time per patient per year spent on ESA administration could be saved by switching patients from a TIW regimen of rHuEPO to a QW regimen [59]. A recent 9-month audit of a clinic in the United Kingdom demonstrated that switching from TIW/BIW SC epoetin alfa to QW or Q2W IV darbepoetin alfa resulted in significant decreases in ESA acquisition costs in 82 patients [60]. Further data are awaited with interest.

After conversion of a Canadian renal program from the use of epoetin alfa (all dose levels) to darbepoetin alfa, total annual retail drug cost savings were estimated at $285 475. Annual savings of $8000 to $9000 per patient were found after conversion to darbepoetin alfa for patients receiving high doses of epoetin alfa (>60 000 IU per month) before conversion. Haemoglobin values did not change significantly after conversion [61].

Fewer injections may also reduce the risk of needlestick injuries to nursing staff and patients over time [62,63]. The availability of improved delivery devices for ESAs is also advantageous to patients and nursing staff. These include the single-use, fully enclosed Aranesp® prefilled SureclickTM autoinjector (Amgen, Inc., Thousand Oaks, CA, USA) that can be used for administration of darbepoetin alfa. This type of autoinjector can eliminate dosing errors, reduce needlestick injuries [64], and facilitate self-administration by patients.



   Discussion
Top
 Abstract
 Introduction
 Clinical trials
 Tolerability
 Pharmacoeconomic studies
 Discussion
References
 
The advent of ESAs has revolutionized the management of anaemia in patients with CKD, improving quality of life and well-being while reducing the need for blood transfusions [2]. Epoetin alfa and epoetin beta have traditionally been administered BIW or TIW because of their short in vivo half-lives. Indeed, this may be the most economical way to use these agents [43,65]. Recent years have seen a general trend towards less-frequent dosing regimens, as these offer patients with CRI greater convenience and comfort. Improved delivery devices now available may facilitate self management. Preliminary data indicate that Q2W ESA administration in dialysis patients may improve operational efficiency and reduce costs in haemodialysis centres. Further exploration of these observations is warranted.

In Europe, darbepoetin alfa is approved for QW or Q2W administration in dialysis patients and QM (SC) use in the maintenance phase of anaemia treatment in patients with CKD not yet receiving dialysis [34]. Indeed, darbepoetin alfa is the only ESA approved for QM administration in the latter setting. The efficacy of these dosing regimens has been established in a number of well-designed studies. It has been common practice in European dialysis centres to administer rHuEPO by the less convenient SC route for cost reasons; thus the option to administer darbepoetin alfa IV without increasing the dose has implications for clinical practice. Theoretically, dialysis patients receiving epoetin alfa or beta QW to TIW may be converted to QW or Q2W darbepoetin alfa without a weekly dose increase regardless of the route of administration selected.

Despite the relatively short half-lives of epoetin alfa and epoetin beta, these agents have also been evaluated for less frequent dosing in patients with CKD, although there are relatively few data from rigorously designed studies. In dialysis patients, SC weekly dosing of rHuEPO may be feasible, but a dose-increase is often required when switching from traditional BIW/TIW schedules [66], which will lead to extra cost. There is no clear evidence to support QW rHuEPO dosing by the IV route. The results of some studies indicate that Q2W rHuEPO is effective in selected CRI patients. However, current data do not support the widespread utilization of either epoetin beta or epoetin alfa in QM regimens. After concerns arose regarding pure red cell aplasia approval for SC administration of EPREX® was withdrawn, and it is approved throughout Europe only for TIW or BIW administration in patients with CKD [67]. However, epoetin alfa has recently been relicensed for SC administration in several European countries, and others are considering relicensing it. Epoetin beta is approved for administration, either at QW intervals or at Q2W intervals in patients already on a stable QW regimen, by the SC route [66].

Thus, in Europe, extended ESA dosing regimens have set new standards in the management of renal anaemia, with the options of QW or Q2W treatment in dialysis patients and Q2W or QM (SC) treatment in CRI patients not yet receiving dialysis. While data are well-established for darbepoetin alfa, further study is required to clarify the optimum frequency of administration for other ESAs in these settings.

Conflict of interest statement. Dr F.C. is scientific consultant, member of steering committees for international clinical trials and/or member of international advisory boards for the following companies: Amgen (Europe), Roche (International) and Shire (International).



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 Abstract
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 Clinical trials
 Tolerability
 Pharmacoeconomic studies
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 References
 

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I. C. Macdougall, D. Padhi, and G. Jang
Pharmacology of darbepoetin alfa
Nephrol. Dial. Transplant., June 1, 2007; 22(suppl_4): iv2 - iv9.
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