Cost-effectiveness of methoxy polyethylene glycol-epoetin β versus conventional epoetin in thetreatment of anaemia secondary to chronic kidneydisease in clinical practiceLaura Lorente-Fernández,1 Emilio Monte-Boquet,1 Isabel Gil-Gómez,1

Amparo Soldevila-Orient,2 José Luís Poveda-Andrés1

1Pharmacy Service, HospitalUniversitario y Politécnico LaFe, Valencia, Spain2Nephrology Service, HospitalUniversitario y Politécnico LaFe, Valencia, Spain

Correspondence toLaura Lorente Fernández,Unidad de atenciónfarmacéutica a pacientesexternos, Servicio de farmacia,Hospital Universitario yPolitécnico La Fe, Edificio C,planta baja, Bulevar Sur,Valencia s/n. 46026, Spain;lorente_lau@gva.es

Received 29 November 2013Revised 29 July 2014Accepted 31 July 2014

To cite: Lorente-Fernández L,Monte-Boquet E, Gil-Gómez I,et al. Eur J Hosp PharmPublished Online First: [pleaseinclude Day Month Year]doi:10.1136/ejhpharm-2013-000426

ABSTRACTObjectives To assess the cost-effectiveness of methoxypolyethylene glycol-epoetin β (CERA) used in routineclinical practice for maintenance of Hb levels in patientswith chronic kidney disease in predialysis and previousstabilised treatment with conventional epoetin. Assecondary objective, we analyse the use of CERA inclinical practice.Methods Retrospective observational study includingall patients receiving conventional epoetin who wereswitched to CERA over a period of 2 years.Demographic, clinical and therapeutic variables werecollected. The main effectiveness outcome chosen wasthe difference between the haemoglobin level withconventional epoetin versus CERA after 24 weeks oftreatment. Economic analysis was performed taking intoaccount only the direct drug acquisition cost, the maincost outcome was the difference of patient/month costwith conventional epoetin versus CERA.Results Sixty-nine patients with a mean age of68 years (35% male) were enrolled in the study. In92.8% of cases, the starting dose used was lower thanthat recommended in the summary of productcharacteristics. Mean haemoglobin at 0 and 24 weekswas 11.9 and 11.7 g/dL, with no statistically significantdifference (−0.2, 95% CI −0.6 to 0.1). With CERA, alower proportion of patients exceeded the haemoglobinlimit of 13 g/dL. The patient/month cost was 159.6€and 169.9€ at weeks 0 and 24, with a difference of10.3€ (95% CI −6.8 to 27.5).Conclusions CERA was as effective as conventionalepoetin for the maintenance of haemoglobin levels after24 weeks of follow-up. Conversion to CERA has led toan increase of 10.3€ the patient/month cost.

INTRODUCTIONAnaemia is a common feature in many patientswith chronic kidney disease (CKD) as it is princi-pally due to reduced renal erythropoietin produc-tion by the diseased kidneys. Its prevalenceincreases with progressive deterioration of renalfunction,1 2 usually appearing when glomerular fil-tration rate is below 30 mL/min. It is generallyreported that anaemia worsens the prognosis ofpatients with CKD as well as negatively impactingtheir quality of life.3

The development of erythropoiesis-stimulatingagents (ESA) has been one of the most importantadvances in the treatment of anaemia since it has

reduced the need for transfusions as well asimproved the quality of life of these patients.4 5

Nevertheless, treatment with ESA is not free of dis-advantages. Thus, high haemoglobin (Hb) levelshave been associated with arterial hypertensionwith risk of hypertensive encephalopathy, venousaccess thrombosis and cerebrovascular events.6 7 Inaddition, generalised use of ESA has resulted in anincrease in the healthcare cost of these patients andrepresents approximately 46.5% of the total cost.8

Conventional non-pegylated ESA have a short half-life and require frequent administration, usually twoto three times weekly, to maintain the Hb concentra-tion stable between 11 and 12 g/dL, as recommendedby current clinical guidelines of the main scientificsocieties.9–11 The incorporation into the therapeuticarsenal of an ESA formed by the addition of amethoxy polyethylene glycol polymer to the mol-ecule of epoetin β has led to a change in the manage-ment of patients with CKD. Methoxy polyethyleneglycol-epoetin β (CERA) acts as a continuous activa-tor of the erythropoietin receptor and is characterisedby a slower association with and a faster dissociationfrom the receptor, with an increased activity in vivo,as well as an increased plasma half-life (about130 h).12 All this confers CERA the advantage that itcan be used in a wide dosing interval, every 15 daysin the correction phase and once-monthly in main-tenance phase,13 which means fewer injections andtherefore a time saving and a potential improvementin the quality of life of these patients.Methoxy polyethylene glycol-epoetin β has been

shown in different clinical trials to be non-inferior toconventional ESA in maintaining Hb levels in previ-ously treated patients with CKD.14–17 Nevertheless,their cost-effectiveness in standard clinical practice isless clear. On the basis of these findings, the purposeof the present study is to assess the cost-effectivenessof CERA used in routine clinical practice for mainten-ance of Hb levels in patients with CKD in predialysisand previous stabilised treatment with conventionalepoetin α or β. As secondary objective, we analyse theuse of CERA in clinical practice regarding CERA con-version factor, number of dose adjustments and per-centage of patients with Hb values higher than thoserecommended in current clinical guidelines.

METHODSWe performed retrospective observational studyconducted in the setting of an outpatient

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pharmaceutical care unit (OPCU) of a polytechnic universitypublic hospital. A preliminary meeting with the nephrologists ofour hospital was carried out in order to determine inclusion cri-teria, variables to collect and evaluation times. The studyenrolled all adult patients (age >18 years) with CKD, not ondialysis, receiving conventional epoetin α or β who wereswitched to CERA over a period of 2 years. We included onlystable patients regarding previous ESA dose and Hb level.Hospital ethic committee approval was obtained before initiat-ing the study.

From patients’ medical charts and drug dispensation recordof the OPCU, the following variables were collected: demo-graphic (age, sex), clinical (creatinine, Hb, ferritin, transferrinsaturation index (TSI)), therapeutic (type of ESA, dose, dosinginterval, treatment time) and economic (monthly direct treat-ment cost). GFR was also determined for each patient using theModification of Diet in Renal Disease (MDRD) study equa-tion,18 and the study sample was categorised by stage of renaldisease according to the National Kidney Foundation-KidneyDisease Outcomes Quality Initiative (NKF-K/DOQI) classifica-tion.9 The MDRD equation is obtained with the knowledge offour parameters: serum creatinine concentration, age, sex andrace. The follow-up period was 24 weeks. Every variable wasrecorded at baseline (immediately before switching ESA).Additionally, therapeutic and economic variables were recordedat 12 (dose titration phase) and 24 weeks (evaluation phase) ofCERA treatment.

As regards the use of CERA in clinical practice, we analysedCERA conversion factor, number of dose adjustments duringthe study period and percentage of patients with Hb valueshigher than those recommended in current clinical guidelines.

To evaluate the effectiveness of CERA, the main outcomechosen was the difference between the Hb level at baseline withconventional epoetin (before the change to CERA) and at24 weeks of CERA treatment, both overall and by CKD stage(figure 1). These timelines were established based on the recom-mendation published in the literature and the design of pivotalclinical trials of CERA.

For the cost analysis, as in Spain the ESA are dispensed onlyin hospital pharmacies, the study was conducted from the per-spective of a hospital pharmacy service. Thus, the costs usedwere the acquisition cost of ESA administered. The economicanalysis was performed taking into account only the direct drugacquisition cost (ex-factory price) from the Spanish drug data-base of Consejo General de Colegios Oficiales de Farmacéuticos(2013). We calculated the patient/month cost as the cost of theunit of dose for each ESA type multiplied by the monthly doseused in each patient. Therefore, the cost per patient per monthwas calculated at baseline (before the change to CERA) and at24 weeks of CERA treatment. The main cost outcome chosenwas the difference between the patient/month cost with conven-tional epoetin versus CERA. For this, a month was consideredas a period of 30 days.

Statistical analysisA descriptive analysis was performed of patient characteristicsrelated to the explanatory variables considered in the study.Quantitative variables were described as median and centiles(25–75%) and qualitative variables as absolute and relativefrequencies.

The comparison of means in the case of quantitative variableswas carried out using parametric (Student–Fisher t test) or non-parametric (Wilcoxon T test) paired tests according to fulfilmentor not the normality assumption. Fisher exact test was used tocompare qualitative variables.

Statistical significance for contrast tests was p<0.05. Statisticalanalysis was performed with the SPSS V.19.0 computer software.

RESULTSDuring the study period, 87 patients on previous treatment withconventional epoetin and meeting inclusion criteria startedtreatment with CERA. Among them, 18 were excluded from thestudy: 14 due to unavailability of Hb data to evaluate the effect-iveness of CERA at 24 weeks, 2 due to discontinuation of medi-cation dispensing at the OPCU and 2 due to changes in ESAtype. Table 1 shows the baseline sociodemographic and clinicaldata of the final study population (n=69).

Prior to conversion to CERA, 65 patients (94.2%) werereceiving epoetin β and the remaining epoetin α. The mediantime on treatment with CERA until the end of the dose titrationphase was 88 days (67–96) and until the end of the evaluation

Figure 1 Treatment scheme andeffectiveness analysis. Hb0, baselinehaemoglobin; Hb3, haemoglobinmonth 3; Hb6, haemoglobin month 6.

Table 1 Baseline sociodemographic and clinical characteristics ofthe study population (n=69)

Variables

Age (years) 68.2 (51.8–79.1)SexFemale 45 (65.2%)Male 24 (34.8%)

Creatinine (mg/dL) 2.0 (1.5–2.6)Glomerular filtration rate (mL/min/1.73 m2) 29.7 (21.8–40.8)Renal disease stage according NFL-K/DOQUIStage 1 2 (2.9%)Stage 2 6 (8.7%)Stage 3 24 (34.8%)Stage 4 32 (46.4%)Stage 5 5 (7.2%)

Iron (mcg/dL) 65.0 (53.0–79.0)Ferritin (ng/mL) 174 (111.5–349.8)TSI (%) 25.5 (19.0–31.8)Haemoglobin (g/dL) 11.8 (11.1–12.7)

Values expressed as number (percentage) or median (25–75 centile).NFL-K/DOQUI, National Kidney Foundation-Kidney Disease Outcomes Quality Initiative;TSI, transferrin saturation index.

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phase was 200 days (175–229). The dose and dosing interval ofconventional epoetin at baseline and of CERA at 0, 12 and24 weeks are described in table 2.

Regarding the conversion factor, figure 2 shows the startingdoses of CERA recommended in the summary of productcharacteristics, according to the previous weekly dose of con-ventional epoetin, and the dose used in the study sample. In 64patients (92.7%), the starting dose used was lower than thatrecommended in the summary of product characteristics.During the 6 months of follow-up of CERA treatment, 32 doseadjustments were made (0.5 changes per patient), 27 (73.3%) toincrease and 10 (24.7%) to decrease the starting dose. No dosechange was made in 56.5% of patients, whereas 33.3% and10.2% had one and two adjustments, respectively.

Mean Hb at the start of CERA treatment in patients treatedwith conventional epoetin was 11.9 g/dL (95% CI 11.6 to12.2). After 12 and 24 weeks of CERA treatment, mean Hb was11.7 g/dL (95% CI 11.3 to 12.1) and 11.7 g/dL (95% CI 11.4to 12.0) respectively, resulting in a mean difference between Hbvalues at baseline and at 6 months of CERA treatment of−0.2 g/dL (95% CI −0.6 to 0.1), which was not statisticallysignificant.

When the study sample was categorised by CKD stage, statistic-ally significant differences were also not found between Hbvalues at baseline and at 24 weeks in any of the categories made(table 3). Patients in stages 1 and 2 and those in stages 4 and 5were grouped in a single category to avoid very small sample sizes.

The percentage of patients with Hb values higher than thoserecommended (11–12 g/dL) in current clinical guidelines9–11

was 40.6 with conventional epoetin versus 36.2 after 24 weeksof CERA treatment (p=0.005). The values and the results ofthe statistical analysis between baseline and week 24 are shownin figure 3.

In our study, CERA was as effective as conventional epoetinin maintaining Hb levels. Therefore, our final economic analysiswas a cost-minimisation analysis.

The patient/month cost at baseline with conventional epoetinwas 159.6€ (95% CI 133.3 to 185.9) and the patient/monthcost at week 24 of CERA treatment was 169.9€ (95% CI 147.8to 192.1). Conversion to CERA in the study populationincreased the patient/month cost by 10.3€ (95% CI 6.8 to27.5).

DISCUSSIONApproximately 50% of non-dialysed patients with CKD presentanaemia.19 These patients often require frequent administrationof ESA subcutaneous injections, which can negatively impact ontheir treatment compliance and quality of life. The number ofinjections and, therefore, the pain associated with them20 arereduced because of the wide dosing interval provided by CERA.

Methoxy polyethylene glycol-epoetin β has been evaluated insix pivotal studies in which it was compared with other ESA,two were carried out in patients receiving treatment for the firsttime and other four in patients who had been previously treatedwith ESA.14–17 In the studies of pretreated patients, CERAmaintained Hb values with the same efficacy as those who con-tinued receiving their previous ESA and there was no overallvariation in Hb concentrations over the duration of the studies.

Table 2 Monthly dose and dosing interval

Conventional epoetin (α/β)Baseline level

CERAWeek 0

CERAWeek 12

CERAWeek 24

Dose (IU) DI (days) Dose (mcg) DI (days) Dose (mcg) DI (days) Dose (mcg) DI (days)

16 000 (9500–24 000) 7 (7–7) 75 (50–100) 30 (30–30) 75 (50–100) 30 (30–30) 75 (50–100) 30 (30–30)18 782.6 (13 115.9) 8.6 (3.2) 75.9 (35.0) 29.0 (3.7) 82.6 (49.9) 29.2 (3.2) 86.93 (53.2) 29.6 (3.7)

Values expressed as median (25–75 percentile) and mean (SD).CERA, methoxy polyethylene glycol-epoetin β; DI, dosing interval.

Figure 2 Conversion factor of convention epoetin to CERA in the study sample. Values expressed as median (25–75 percentile) and mean (SD).CERA, methoxy polyethylene glycol-epoetin β.

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These results are similar to those found in our study, thoughthey are not comparable because neither the follow-up periodnor baseline characteristics of the patients included in the trialswere equal.

The change in the mean Hb concentration in our study wassimilar to that published by Fliser et al21 in the MIRACEL studywith pretreated patients on dialysis: 11.7, 11.6 and 11.4 g/dL atbaseline, 5 and 7 months, respectively. Likewise, in the study ofPadullés-Zamora et al22 in patients previously treated with ESA,mean Hb before starting CERA was 11.2 and 11.4 g/dL at12 months (p=0.846). Roger et al23 compared CERA oncemonthly versus darbepoetin twice monthly in non-dialysedpatients, demonstrating the non-inferiority of CERA to darbe-poetin, as well as a similar adverse effect profile. Choi et al24

also concluded that conversion from ESA with shorter half-lifeto subcutaneous once-monthly CERA in predialysis CKDpatients can efficaciously maintain Hb. Frimat et al,25 in theOCEANE study, confirmed the efficacy and safety of CERA inroutine clinical practice. All these data are in agreement withours since no statistically significant differences were foundbetween Hb levels at week 0 with conventional epoetin and at24 weeks with CERA. Nor when we categorised the studysample by CKD stage were statistically significant differencesobserved, so it does not seem that the severity of disease influ-ences the effectiveness of CERA.

The percentage of patients with Hb values above 13 g/dL, thesafety limit established by the main clinical practice guidelines,was lower at 6 months of CERA treatment (13%) than at the

start of treatment (14.5%), although this difference was not stat-istically significant (p=0.609, figure 3). In addition, the percent-age of patients with Hb values within the recommended range(11–12 g/dL) was higher with CERA at week 24 (63.8%) thanfor conventional epoetin at baseline (59.4%) and this differencewas statistically significant (p=0.005, figure 3). In the study ofPadullés-Zamora et al, the percentage of patients with Hb above13 g/dL at weeks 12 and 24 was lower than ours: 10% and 6%,respectively.

Regarding iron requirements, international organisations rec-ommend for patients not undergoing dialysis to maintain aserum ferritin level above 100 ng/mL and/or a TSI greater than20%.9 10 It should be noted that there were only 49 patients(71%) in the study sample at baseline who met those recom-mendations. Furthermore, no ferritin data were available in 23patients (33%), no TSI data in 13 patients (19%) and neitherferritin or TSI in 10 patients (20%).

As for the conversion factor of conventional epoetin to CERA,it is notable that 92.8% of the starting doses used in the presentstudy were lower than those recommended in the summary ofproduct characteristics. We observed a trend towards using lowerdoses than those recommended and this fact is consistent withthe results of Padullés-Zamora et al22 reporting doses 39.2%lower than expected. It seems reasonable that most dose adjust-ments in our study (73.3%) were made to increase the dose.During the 6 months of our study follow-up, the mean numberof dose changes per patient (0.5 changes/patient) was lower thanthat reported by Fliser et al21 (2 changes/patient). Many studies

Table 3 Analysis of Hb concentration in sample categorised by CKD stage

Hb (g/dL)Mean (95% CI)

Hb difference* (g/dL)Mean (95% CI)

Stages 1 and 2 (n=8) Baseline Hb conventional epoetin 11.65 (10.96 to 12.33) −0.24 (−1.34 to 0.86)Hb week 24 CERA 11.41 (10.45 to 12.37) p=0.735

Stage 3 (n=24) Baseline Hb conventional epoetin 12.00 (11.53 to 12.50) 0.004 (−0.600 to 0.609)Hb week 24 CERA 12.01 (11.43 to 12.58) p=0.735

Stages 4 and 5 (n=37) Baseline Hb conventional epoetin 11.97 (11.55 to 12.39) −0.34 (0.83 to 0.14)Hb week 24 CERA 11.62 (11.19 to 12.05) p=0.261

Wilcoxon rank-sum test.*Hb difference: (baseline Hb—Hb week 24).CERA, methoxy polyethylene glycol-epoetin β; CKD, chronic kidney disease; Hb, haemoglobin.

Figure 3 Patient distribution by haemoglobin level. Values expressed in absolute and relative frequencies. Fisher’s exact test. CERA, methoxypolyethylene glycol-epoetin β.

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have been conducted to compare equivalences in terms of dosebetween different ESA and their economic impact,26–29 but wehave found only one that directly compares dose and cost ofthese ESA for predialysis patients in daily clinical practice.30 Inour study, as the effectiveness was the same, it was of utmostimportance to analyse the true cost of CERA in treatment ofanaemia secondary to CKD. Especially within the setting of aneconomic crisis, where the search for efficiency has become oneof the main objectives of professionals and health authorities.The results of our study showed an increase of 10.3€ in thepatient/month cost of CERA therapy compared with previousESA therapy, but this difference was not statistically significant.Escudero-Vilaplana et al,30 in a recent cost minimisation analysispublished, also found a CERA monthly cost (147.5€) higher thanepoetin (103.2€), but in this case the difference was statisticallysignificant (p<0.05). This could be because each ESA cost, apartfrom the ex-factory price, depends directly on the dose pre-scribed, that is, the dose that each patient finally receives tocorrect the anaemia.

The conversion to CERA in our study (69 patients) resultedin an increase of 6.5% the patient/month cost, but we must takeinto account that the economic analysis was performed onlywith the direct drug acquisition cost, excluding other costs suchas the administration. In this regard, it is evident that CERA hasadvantages since its frequency of administration is less than con-ventional epoetin and this could be cost saving.

In our study, the cost of treatment was calculated from theex-factory price of the different ESA, the official price commonfor all hospitals, without considering the discounts derived frompossible negotiations or centralised purchasing procedures. Inthis regard, we choose this price because the results of the eco-nomic analysis may be affected to a greater or lesser extentdepending on the amount of these discounts. On the otherhand, although the dose used in conversion to CERA was lowerthan those recommended in the summary of product character-istics, the patient/month cost was calculated at 24 weeks of

CERA treatment, after the pertinent dose adjustments for Hbmaintenance in the optimal range.

Our study has several limitations. First, the retrospectivedesign. Furthermore, Hb levels evaluated at a specific time donot reflect adequate management of anaemia in patients receiv-ing ESA, where it is more appropriate to perform serial mea-surements scheduled over time. Another limitation, as alreadymentioned, is that not all patients had correct iron stores atbaseline, and this could have affected the effectiveness of theESA since it is one of the main causes of inadequate response toESA. In any case, the objective of the present study was to assessthe cost-effectiveness of CERA in routine clinical practice (reallife), and this is its major strength.

The results of the study should not be generalised as theywere obtained from the clinical practice of our hospital. Eachcentre should adjust these results to their real purchase costs, aswe used ex-factory price to calculate costs. Furthermore, infuture pharmaco-economic research it would be interesting toadd indirect cost as that derived from personal, administrationor visits as well as quality of live data.

In conclusion, in our study CERA was as effective as conven-tional epoetin for the maintenance of haemoglobin levels after24 weeks of follow-up. Conversion to CERA has led to anincrease of 10.3€ the patient/month cost.

Contributors This work was carried out as follows: planning (LLF, EMB, ASO),data collection (LLF), analysis (LLF, EMB), manuscript drafting and editing (LLF, EMB,IGG, ASO, JLPA). All the authors contributed to the approval of the final version.

Funding This work was supported by grants from Roche SA.

Competing interests None.

Patient consent Obtained.

Ethics approval Ethical Committee of Clinical Research Hospital Universitario yPolitécnico La Fe.

Provenance and peer review Not commissioned; externally peer reviewed.

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Key messages

What is already known on this subject▸ Methoxy polyethylene glycol-epoetin β (CERA) use

represents an innovation concerning the clinicalmanagement of anaemia in patients with chronic kidneydisease as it presents the advantage of a wide dosinginterval, which means fewer injections and therefore a timesaving and a potential improvement in the quality of life ofthese patients.

▸ CERA efficacy and safety has already been shown in severalclinical trials in which it was compared with othererythropoiesis-stimulating agents.

What this study adds▸ Our study provides evidence of the cost-effectiveness and

use of CERA in routine clinical practice, away from thecontrolled environment of the clinical trials.

▸ CERA is as effective as conventional epoetin for themaintenance of haemoglobin levels after 24 weeks offollow-up, and although there is an increased patient/monthcost, it is not statistically significant.

▸ Our results may be useful in the management andoptimisation of treatment with CERA.

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29 Cuesta C, Poveda JL, García J, et al. Análisis de minimización de costes dedarbepoetina alfa frente a epoetina alfa en pacientes con insuficiencia renal crónicasometidos a hemodiálisis. Farm Hosp 2010;34:68–75.

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6 Lorente-Fernández L, et al. Eur J Hosp Pharm 2014;0:1–6. doi:10.1136/ejhpharm-2013-000426

Original article

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doi: 10.1136/ejhpharm-2013-000426 published online August 21, 2014Eur J Hosp Pharm

 al.Laura Lorente-Fernández, Emilio Monte-Boquet, Isabel Gil-Gómez, et clinical practicesecondary to chronic kidney disease inepoetin in the treatment of anaemia

versus conventionalβglycol-epoetin Cost-effectiveness of methoxy polyethylene

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