Abstract
In May 2009 for financial reasons, the epoetin product used for hemoglobin (Hb) maintenance in our renal dialysis unit was changed from epoetin beta to epoetin alfa. Although widely believed that the dosage requirements are the same, we undertook a retrospective analysis to investigate whether the dosage requirements in chronic renal failure patients were comparable for both preparations. We studied 128 stable end-stage renal failure patients on hemodialysis (three times per week) receiving erythropoietin therapy to maintain their Hb at 11–12.5 g/dL. Patients were excluded if within the study period they developed signs of infection, bleeding, required blood transfusion, were under-dialyzed, or required hospital admission. Regular monthly Hb concentrations and hematocrit (Hct) levels were measured for each patient. The weekly EPO index (defined as weekly epoetin dose/mean monthly Hct) was derived for each patient, before and after regime change. Of the 128 patients in end-stage renal failure, 79 were included in the study. There was no significant difference between the two preparations in terms of Hct level achieved (p = 0.15). However, the median weekly epoetin dose requirement increased from 6733 (range 750–30,000) IU/week to 9000 (250–30,667) IU/week (p < 0.001). EPO index similarly increased from 20,465 (2500–130,846) IU/week/% to 27,073 (729–98,937) IU/week/% (p < 0.001). Our study showed that a higher dose of epoetin alfa was needed to maintain target Hb concentration.
INTRODUCTION
Anemia is a complication of end-stage renal failure and is currently managed by administration of erythropoietin-stimulating agents (ESA) and iron products to achieve target hemoglobin (Hb) levels greater than 11 g/dL. Treatment of renal anemia with epoetin products is associated with reductions in patient mortality, hospital admission, and blood transfusion requirements, in addition to improvement in quality of life and well-being.Citation1 There are currently over 40,000 renal failure patients in the United Kingdom requiring erythropoietin,Citation2 at an annual cost of £2300 per patient per annum.Citation3
Recently, erythropoietin alpha (Eprex) has been made available to our hospital at a cheaper price, and this mandated a change from erythropoietin beta to the alpha preparation. Current evidence suggests that epoetins alfa and beta have the same clinical efficacy; however, guidelines do not differentiate between the two and dosages are assumed to be comparable.Citation4–6 As cost savings are predicated on the basis of equal efficacy, we decided to test this hypothesis by measuring the dose of Eprex and comparing that to the dose of the beta preparation needed to maintain Hb levels, as recommended by current European Association Guidelines.
MATERIALS AND METHODS
The Mid Essex Renal Dialysis Centre is a regional dialysis centre serving a population of 400,000 and currently has 140 patients on hemodialysis annually. In May 2009, there were 130 patients on renal dialysis three times per week, each receiving intravenous epoetin twice or three times weekly to maintain Hb levels within a range of 11–12.5 g/dL (Hct > 33%), in accordance with European Guidelines.Citation6 Serum iron and ferritin levels were also routinely monitored and ferritin level maintained within the range of 200–500 µg/L.
In May 2009, the epoetin product for all dialysis patients in our unit was changed from epoetin beta (NeoRecormon; Roche, Herts, UK) to epoetin alfa (Eprex; Janssen-Cilag, Bucks, UK). We continued to administer epoetin at the same frequency. The dosage of alfa epoetin initially administered was identical to the previous beta dosage, but was subsequently adjusted to maintain Hb concentrations at the usual unit target level of 11 g/L.
We recorded routine Hb concentration, hematocrit (Hct) levels, and the required epoetin dose for all the patients involved in the drug change. Using this, we calculated the EPO index for each patient (EPO index being defined as weekly erythropoietin dose/mean monthly Hct). Data were collected for a 11-month period; firstly the period from December 2008 to April 2009 (i.e., the 5 months preceding the change to the epoetin alfa) and then for the period from June to November 2009 (i.e., the 6-month period after the change to the epoetin alfa).
Only data from patients who were in maintenance phase of epoetin therapy for a minimum of 3 months before the regimen change were used. Patients were excluded from analysis if they developed signs of infection (WCC > 12 or raised CRP) within the study period, had major issues with access requiring surgical intervention, signs of bleeding, required blood transfusion, were under-dialyzed (KT/V < 1.1), or required hospital admission.
Mean values for Hb, Hct, and EPO index (for epoetin beta) were derived for each patient for the period from December 2008 to April 2009, and for the period from June 2009 to November 2009 (for epoetin alfa). Costing was calculated using the price tendered to the hospital for each product. Epoetin beta was provided to the hospital at a rate of £4.0 per 1000 units, and Epoetin alfa for £2.0 per 1000 units.
The dose requirements (units/week) of epoetins alfa and beta were calculated and the figure for the overall cost/week was derived from the dose requirements. Data were expressed as mean (standard deviation) or median (range), as appropriate. The dosage for each patient before and after the regimen change was compared using paired t-test or Wilcoxon's signed rank sum test as appropriate, and a value of p < 0.05 was considered significant (Stata version 11).
RESULTS
Of the 128 patients on dialysis, 79 were eligible for inclusion in the study. Our population demographics for primary renal diagnosis and associated comorbidities reflected a similar distribution found in the rest of the United Kingdom.
The Hct concentrations for each individual patient were stable over the 12-month period, and there was no difference between preparations in mean Hct levels achieved. The mean (SD) for Hct concentration achieved for epoetin beta was 0.34 (0.31) and 0.35 (0.24) for epoetin alfa (paired t-test p = 0.15). Overall the median weekly beta epoetin dose requirement was 6733 IU/week (range of 750–30,000 IU/week), whereas the corresponding requirement for epoetin alfa was 9000 U/week (range 250–30,667, p < 0.001). The EPO index similarly increased from 20,465 (2500–130,846) IU/week/% to 27,073 (729–98,937) IU/week/% for epoetins beta and alpha, respectively (p < 0.001). The median cost in units/week was £26.93 (3–120) and £18 (0.5–61) for epoetins beta and alfa, respectively.
DISCUSSION
In end-stage renal failure patients, we have shown that both epoetins alfa and beta were effective at achieving target Hb levels between 11 and 12.5 g/dL, in accordance with European Association Guidelines.Citation6 However, it appears that target Hb levels were achieved using significantly lower doses of epoetin beta (6733 units/week) compared with epoetin alfa (9000 units/week).
The higher dose requirements for the alfa preparation were supported by Halstenson and colleaguesCitation7 who found in healthy volunteers that alpha epoetin had a larger volume of distribution than the beta preparation (16.9% vs. 7.7%), but that beta epoetin had a 20% longer half-life. More recent work by Sorgel and colleaguesCitation8 has shown both products to be bioequivalent. They concluded that both are equally efficacious and could be used interchangeably. However, both these studies have been performed on healthy volunteers. With worsening creatinine clearance and renal failure, it has been shown that epoetin responsiveness is reduced and differs with normal individuals.Citation9 Therefore, a comparison of the potency of epoetin products in healthy individuals may not transfer accurately to renal failure patients.
Although our study was performed on patients undergoing intravenous administration of epoetin, our findings are potentially relevant to subcutaneous route. Pharmacokinetic studies comparing subcutaneous and intravenous administration of epoetin products show that the bioavailability of both epoetin preparations is lower with subcutaneous administration. However, the half-life is longer with subcutaneous administration resulting in lower dose requirements than with the intravenous route.Citation10
The large observed inter-patient variation in epoetin therapy, and therefore of EPO index, is a characteristic of patients on hemodialysis and is consistent with the findings of other authors.Citation11,Citation12 EPO index allows us to use a single variable to analyze response to epoetin therapy and can be used as a marker of response to epoetin therapy in populations on maintenance hemodialysis.Citation13 Despite the higher dose of Eprex, we still achieved a higher cost saving using this preparation. However, in our study, the cost saving was lower than that expected on the assumption of equal efficacy.
There are a number of limitations of this study. It is retrospective and single centered. As in any renal failure population the large inter-patient variation results in many outliers on high doses, thus skewing the results in a small data set. The longitudinal and retrospective design of our study does not eliminate natural changes seen in disease progression and epoetin responsiveness. However, all previous work comparing these epoetin products have used cohorts of no larger than 80 individuals,Citation7,Citation8 which makes our study one of the largest. As there are currently no large-scale randomized studies comparing these products on renal failure patients, we believe our findings support the need for these to be carried out.
In summary, our study has shown that both epoetins alfa and beta achieved target Hct levels. However, epoetin beta achieved this with significantly lower doses. Although only intravenous route data were analyzed, there is good evidence to suggest that a similar pattern would be seen after subcutaneous administration. We recommend that differences between the preparations should be incorporated in future guidelines.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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