Extended epoetin alfa dosing in chronic kidney disease patients: a retrospective review

Michael Germain1, C. Venkata Ram2, Sarbani Bhaduri3, K. Linda Tang3, Mark Klausner4 and Mario Curzi5

1 Western New England Renal and Transplant Associates, Springfield, MA, 2 Dallas Nephrology Associates, Dallas, TX, 3 Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ, 4 Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ and 5 Diablo Nephrology Medical Group, Walnut Creek, CA, USA

Correspondence and offprint requests to: Michael Germain, MD, Western New England Renal and Transplant Associates, 300 Birne Avenue, Suite 300, Springfield, MA 01107, USA. Email: Michael.Germain{at}bhs.org



   Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. The effectiveness of extended dosing of epoetin alfa beyond once-weekly (QW) has not been well explored in patients being treated for anaemia of chronic kidney disease (CKD). The current study was undertaken to assess the effectiveness of extended dosing in maintaining haemoglobin (Hb) levels in this population.

Methods. A retrospective chart review was conducted to assess the efficacy of extended epoetin alfa dosing in patients being treated for CKD-related anaemia. Eligible patients were to have received epoetin alfa once every 2 weeks (Q2W), 3 weeks (Q3W), 4 weeks (Q4W), or >Q4W administered subcutaneously for at least 3 months to maintain Hb ≥ 11.0 g/dl. Patients were ≥18 years with serum creatinine 1.5 to 6.0 mg/dl for females and 2.0 to 6.0 mg/dl for males, and were not receiving renal replacement therapy. Epoetin alfa dose and dosing frequency were adjusted during treatment at the clinician's discretion. For analysis, patients were stratified into dosing groups based on their most dominant dosing regimen.

Results. 243 patients (mean age, 71.5 years; 79% white, 54% female) who received extended epoetin alfa dosing for a mean of 10.3 months were eligible for analysis. Mean baseline estimated glomerular filtration rate and mean serum creatinine were 21.2 ml/min/1.73 m2 and 3.1 mg/dl, respectively. Primary causes of CKD included hypertension (36%) and diabetes (28%). Most patients (82%) receiving an extended epoetin alfa regimen maintained Hb ≥11.0 g/dl. The most common dosing regimen was Q2W (51%). Mean Hb for each dosing group was maintained between 11.6 g/dl and 12.4 g/dl during the study, and glomerular filtration rate remained stable. Epoetin alfa was well tolerated across all groups.

Conclusions. Data from private community nephrology practices showed that extended epoetin alfa dosing effectively maintained Hb ≥11.0 g/dl in 82% of these selected patients being treated for anaemia of CKD.

Keywords: anaemia correction; chronic renal disease; epoetin; epoetin dosage; haemoglobin



   Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Anaemia is a frequent complication of chronic kidney disease (CKD), occurring in ~47% of patients in the USA with CKD prior to dialysis [1,2]. Anaemia of CKD primarily occurs because inadequately functioning kidneys are unable to produce adequate amounts of endogenous erythropoietin to support erythropoiesis [3]. Anaemia associated with CKD has been shown to be negatively associated with kidney function decline, cardiac function, exercise capacity, cognitive function, quality of life and mortality [4]. Thus, current guidelines support efforts to correct even mild forms of anaemia in this population to prevent or ameliorate many of these adverse outcomes [4].

Recombinant human erythropoietin (r-HuEPO, epoetin alfa) is biologically and immunologically equivalent to endogenous erythropoietin [5] and is relatively safe and effective for the treatment of anaemia of CKD when used according to accepted dosing guidelines [4,6]. In patients with CKD, treatment of anaemia with epoetin alfa has been associated with decreased hospitalization risk and morbidity [7,8] and improved quality of life [9–11], and may slow kidney disease progression [12,13] and improve survival [14]. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) recommends the use of epoetin therapy to achieve target haemoglobin (Hb) levels of 11–12 g/dl and haematocrit (Hct) levels ranging from 33 to 36% in this population [4].

In patients with CKD-associated anaemia, epoetin alfa therapy administered once weekly (QW) effectively increases Hb levels and improves quality of life, while potentially enhancing compliance compared with more frequent administration regimens [4,15]. However, the effectiveness of extended dosing of epoetin alfa beyond QW has not been well explored in this population. Data from a small, community-based study (N = 64) suggested that less frequent, extended epoetin alfa dosing regimens [i.e. once every 2 weeks (Q2W), 3 weeks (Q3W), 4 weeks (Q4W) or >Q4W] may be effective in maintaining a target Hb level of 11–12 g/dl in CKD patients not on dialysis. In this study, all patients presenting with baseline Hb levels <10 g/dl initially received epoetin alfa 100–150 U/kg QW until Hb levels were ≥11 g/dl for two consecutive measurements [16]. Following this, the epoetin alfa dosing regimen was extended to Q2W and the dose was increased by 50%. If Hb was maintained at ≥11 g/dl, the epoetin alfa dosing was extended to Q4W with a dose increase of 50%. If Hb was not maintained at ≥11 g/dl on Q4W dosing, patients were changed to Q3W dosing. With this protocol, Hb was maintained at 11–12 g/dl for up to 1 year [16]. Mean final Hb levels achieved with QW, Q2W, Q3W and Q4W intervals were 10.3, 11.1, 11.7 and 12.0 g/dl, respectively, and, in patients with >6 months of follow-up, 88% were receiving epoetin alfa Q2W or less frequently [16]. Extended dosing intervals appeared to correlate with significantly higher Hb levels (P<0.05), as well as decreasing monthly epoetin alfa requirements (reduced from 57 028 U/month with QW administration to 17 542 U/month with Q4W administration, P<0.05) [16]. Possible explanations for these correlations were not reported; however, these data support the premise that extended epoetin alfa dosing can effectively maintain target Hb levels of 11–12 g/dl in patients being treated for CKD-related anaemia. In an effort to better understand current clinical practice with regard to extended epoetin alfa dosing, this retrospective review was undertaken to evaluate the clinical usage and efficacy of extended dosing (Q2W, Q3W, Q4W and >Q4W) with epoetin alfa (PROCRIT®, Ortho Biotech Products, L.P., Bridgewater, NJ, USA) in patients with anaemia due to CKD.



   Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study design and patient eligibility
This retrospective chart review collected data on patients with anaemia of CKD from private community nephrology practice study sites across the USA. Practices with experience in treating anaemia with epoetin alfa in pre-dialysis CKD patients were invited to participate. Thirteen sites ultimately participated and collected data on 278 patients. Specific reasons for sites not participating included, but were not limited to, no interest, lack of data and no response from invited sites. All patients who were at least 18 years of age with CKD-associated anaemia were screened against the eligibility criteria for study participation. The definition of CKD was serum creatinine (Scr) 1.5–6.0 mg/dl in females and 2.0–6.0 mg/dl in males prior to initiation of epoetin alfa therapy. Eligible patients were receiving Hb maintenance therapy with an extended epoetin alfa dosing regimen (Q2W, Q3W, Q4W or >Q4W) subcutaneously for at least 3 months. Patients were not on renal replacement therapy prior to or during the time period reflected by the data. Those who met these criteria were asked to participate in the chart review (i.e. have data from their medical records collected). Each individual study site selected which patients to invite to participate.

Epoetin alfa dose and dosing frequency had been adjusted during Hb maintenance at the clinician's discretion. Oral or intravenous iron supplementation had been administered at the clinician's discretion to maintain adequate iron stores to support erythropoiesis. Hospitalization data [including number of and reasons for hospitalization(s)] and evidence of CKD progression [including changes in estimated glomerular filtration rate (GFR), serum and urinary albumin, serum blood urea nitrogen (BUN) and Scr] also had been collected at the clinician's discretion. The chart review was reviewed and approved by each Independent Ethics Committee and/or Institutional Review Board, and conducted in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines and the International Conference on Harmonisation Guidelines. All patients provided written informed consent prior to data collection.

Data collection
The following data were collected from computerized patient record systems and paper medical records: demographics, past medical history and epoetin alfa doses at initiation and throughout at least 3 months of maintenance therapy, Hb, iron, total iron binding capacity (TIBC), ferritin, transferrin saturation, serum albumin, BUN, Scr, vital signs, concomitant medications, hospitalizations and transfusion history. Estimated GFR was calculated based on data collected from medical records using a modified MDRD equation [17].

Statistical analyses
Data were recorded using Microsoft Excel® (Microsoft Corporation, Redmond, WA, USA) and analysed using the most recent version of Statistical Analytical Software (SAS Institute, Cary, NC, USA). Descriptive statistics were used to summarize demographics and laboratory evaluations. Causes of CKD, medical history and concurrent diseases were summarized by disease frequencies and distributions. For the analysis of the results, patients were stratified into dosing groups according to their most dominant dosing regimen [defined as the most frequently administered dosing regimen for each patient (i.e. QW, Q2W, Q3W, Q4W or >Q4W)]. The efficacy of extended dosing regimens and clinical factors associated with Hb maintenance were assessed by evaluating mean values for Hb, Scr and estimated GFR, mean epoetin alfa dose per dosing interval and per 4-week period, and the percentage of patients maintaining Hb ≥11.0 g/dl in each extended dosing group during the maintenance phase of therapy. A dosing interval was defined as the number of days between each two doses of epoetin alfa. Estimated values for GFR were calculated using the following modified MDRD equation [17]:

Mean Hb, Scr and estimated GFR values and 95% confidence intervals were calculated. The paired t-test was used for within-group comparisons. Parameters across different dosing groups were compared using a one-way analysis of variance (ANOVA), followed by pairwise comparisons based on least square means.



   Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Demographics and characteristics
Data from 278 patients were collected, and 243 (87.4%) patients were evaluable for efficacy in this retrospective review. Data from 35 (12.6%) patients were excluded from efficacy analyses due to missing or ineligible Scr (n = 24) and epoetin alfa treatment duration <3 months (n = 11). Patient demographics and characteristics are shown in Table 1. Dosing groups were similar with respect to age, sex, race and cause of CKD (P>0.05). For all patients, the mean age was 71.5±12.8 years; 53.9% were female and 78.9% were white. The primary causes of CKD were hypertension (35.8% of patients) and diabetes (28.4% of patients). Seventeen (7.0%) patients had received a mean of 1.4±0.7 transfusions prior to epoetin alfa therapy (mean number of units per patient, 3.5±1.8).


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Table 1. Patient demographics and baseline characteristics

 
Epoetin alfa dosing
Of the 243 patients evaluable for efficacy, 222 (91.4%) received a dominant epoetin alfa dosing regimen for a mean of 10.3±5.3 months. Some patients had received periods of QW dosing in addition to Q2W, Q3W or Q4W dosing during the time period reflected by the data, which made them eligible for inclusion in this analysis. Patients were categorized based on the dosing regimen they received most frequently. Thus, the most common epoetin alfa dosing regimen was Q2W (51.0%), followed by QW (15.2%), Q4W (12.3%) and >Q4W (3.7%) (Table 2). In patients who were able to be dosed less frequently, the mean total epoetin alfa dose administered per 4-week period was less. The mean epoetin alfa dose per 4-week period was 44 954 U for QW, 36 836 U for Q2W, 32 846 U for Q3W, 19 178 U for Q4W and <19 404 for >Q4W dosing (Table 3). Of the 243 evaluable patients, 109 (44.9%) required at least one epoetin alfa dose (mean 2.7±2.5 doses) to be withheld (Table 3). The mean Hb level in these patients was 13.1±1.0 g/dl at the time the dose was withheld. The most common reason for withholding an epoetin alfa dose was elevated Hb or Hct (n = 81; 71.7%).


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Table 2. Efficacy results stratified by dominant epoetin alfa dosing regimen

 

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Table 3. Epoetin alfa doses stratified by dominant epoetin alfa dosing regimen

 
Haematological parameters
Across all dosing regimens, Hb levels were maintained between the first maintenance dose and the last maintenance dose (Figure 1). During the maintenance phase, the mean Hb ranged between 11.6 and 12.4 g/dl across all dosing regimens (Table 2). The Hb change between the first and last maintenance dose was no greater than 0.5 g/dl for all dosing regimens except QW. The Hb at first maintenance dose for QW was significantly lower than the Hb of other dosing groups (P<0.05), and increased 1.9 g/dl during the maintenance phase. The final mean Hb level was 11.8±1.1 g/dl for all patients (P = 0.0110 vs mean Hb at first maintenance dose, which was 11.5±1.2 g/dl). Overall, 181 (81.9%) patients receiving an extended epoetin alfa regimen maintained Hb levels ≥11.0 g/dl during the maintenance phase of treatment (Figure 2).



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Fig. 1. Mean Hb levels for all patients and stratified by epoetin alfa dosing regimen at pre-dose (prior to epoetin alfa therapy), first maintenance dose and at last maintenance dose. *Of 243 evaluable patients, 21 (8.6%) did not have a dominant dosing regimen and are included in the ‘all patient’ assessment only. QW = once weekly; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks. {dagger}P 0.0001 vs first maintenance dose; {ddagger}P = 0.0477 vs first maintenance dose.

 


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Fig. 2. Percentage of patients maintaining Hb levels ≥11.0 g/dl during extended epoetin alfa dosing. *Of 243 evaluable patients, 21 (8.6%) did not have a dominant dosing regimen and are included in the ‘all patient’ assessment only. QW = once weekly; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks.

 
Laboratory parameters
The distribution of evaluable patients within mean estimated GFR categories overall and by dominant dosing regimen is shown in Table 2. No clinically significant changes in estimated GFR were observed from the first epoetin alfa maintenance dose to final assessment. There were no significant differences between dosing groups with respect to mean estimated GFR or Scr during the maintenance phase, although the mean Scr tended to be lower in the less frequently dosed patients.

No significant changes in ferritin or transferrin saturation were observed from the first epoetin alfa maintenance dose to final assessment. Table 2 presents the proportion of patients in each dosing group with transferrin saturation <20% and serum ferritin <100 ng/ml during the maintenance phase. There was a significant difference between ferritin levels during maintenance therapy for patients in the Q4W group (226.2 ng/ml) vs the QW (132.0 ng/ml; P = 0.0289) and Q2W groups (142.8 ng/ml; P = 0.0273). Significant differences were also observed for transferrin saturation during maintenance therapy for patients in the Q4W group (34.2%) vs the QW (17.4%) and Q2W (23.2%) groups (P<0.0001).

Transfusion requirements
Seven (2.9%) patients required a mean of 1.4±0.8 transfusions during epoetin alfa maintenance therapy. The mean number of units transfused per patient was 3.3±1.5. One patient in the QW group who had been hospitalized for a bleeding ulcer received one transfusion of four units during the maintenance phase. The remaining six patients were in the Q2W group and received a mean of 1.5±0.8 transfusions (3.2±1.6 units per transfusion).

Safety
Epoetin alfa therapy was well tolerated in all dosing groups. The mean systolic blood pressure for all patients was 138.1 mmHg at the beginning of the maintenance phase and 138.5 mmHg at the last recorded value. The mean diastolic blood pressure for all patients was 72.8 and 72.6 mmHg at both time points, respectively. For all patients and for each dosing group, there were no statistically significant changes in either systolic or diastolic blood pressure during the study. Hypertension, defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg, was noted in 41.6% of patients (mean Hb, 11.6±0.9 g/dl) during the maintenance phase. Hypertension was noted in 37.6% of patients prior to epoetin alfa therapy, 43.6% of patients at the first extended maintenance dose and 43.6% of patients at the last recorded maintenance dose. The most common antihypertensive medications were angiotensin-converting enzyme inhibitors (38.3% of patients), dihydropyridine derivative calcium channel blockers (37.4%), selective beta-blocking agents (34.6%) and angiotensin II antagonists (33.7%). There were no significant differences between dosing groups with respect to the types of antihypertensive medications received. Overall, 35 (14.4%) of the 243 evaluable patients required at least one hospitalization during epoetin alfa treatment. There were no significant differences in the incidence of hospitalizations among dosing groups. The most common diagnoses resulting in hospitalization were arterio-venous fistula operation (2.9%), congestive heart failure (1.6%), weakness (1.6%), chronic renal failure (1.2%), cerebrovascular accident (1.2%) and bradycardia (1.2%). Three patients died after the study period: two in the Q2W group (one due to heart failure, and the other due to unknown causes) and one in the Q4W group (due to unknown causes).



   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This retrospective analysis of 243 patients with CKD-related anaemia suggests that extended epoetin alfa dosing effectively maintains Hb levels ≥11.0 g/dl and is well tolerated. Overall, 81.9% of patients maintained Hb levels ≥11.0 g/dl when epoetin alfa was administered using extended dosing regimens for at least 3 months. A trend was observed in that patients with higher Hb, lower Scr and higher transferrin saturation received less frequent epoetin alfa dosing. This may suggest that, if aggressive iron replacement was given, more patients could have received less frequent dosing. Notably, there were no clinically significant changes in estimated GFR values from the first maintenance dose to the end of the maintenance period in any of the dosing groups, suggesting that kidney function did not deteriorate significantly during the study (for evaluable patients, a mean of 10.3 months).

Recently, results from a prospective, randomized, open-label study of extended epoetin alfa dosing regimens for maintenance phase treatment of anaemia of CKD became available. At enrolment, patients had Scr 1.5–6.0 mg/dl for females or 2.0–6.0 mg/dl for males, were not receiving dialysis, had Hb ≥11.0 g/dl ±10% for three consecutive values, and had received epoetin alfa for ≥2 months. Patients were randomized to one of four subcutaneous dosing regimens for up to 16 weeks: 10 000 U QW, 20 000 U Q2W, 30 000 U Q3W or 40 000 U Q4W. Mean baseline Hb was similar across groups (11.9 g/dl). Approximately 90% of patients in the QW and Q2W groups and >75% of patients in the Q3W and Q4W groups maintained Hb levels ≥11.0 g/dl with extended epoetin alfa dosing. Quality of life was maintained or improved across all dosing groups. Extended epoetin alfa dosing was well tolerated, with no difference in the occurrence of adverse events between groups [18]. The important difference between this randomized study and the current study is that patients in the former study were randomly selected to receive a specific dosing regimen, regardless of their sensitivity to epoetin alfa. In the current study, patients received an extended dosing regimen and dose based on their response to prior doses of epoetin alfa.

The retrospective analysis reported here provides an overview of community nephrology practice in the USA and suggests that epoetin alfa is commonly administered at extended dosing intervals to patients being treated for anaemia of CKD. A study comparing the pharmacokinetic profiles of erythropoietin molecules showed that half-life is inversely related to binding affinity for the erythropoietin receptor [19]. When administered intravenously to chronic renal failure patients, the elimination half-life of epoetin alfa ranges from 4 to 13 h [20]. However, epoetin alfa has a 4.3-fold greater binding affinity for the erythropoietin receptor than darbepoetin alfa [19]. Overall, the data reviewed in this study show that extended epoetin alfa dosing effectively maintains Hb levels ≥11.0 g/dl, suggesting that clinical efficacy may be a result of binding affinity, as well as half-life. In addition, epoetin alfa appears to be well tolerated when administered over extended dosing intervals. Despite the retrospective study design and potential selection bias resulting from site selection of patients, these results are consistent with those of previous studies of extended dosing of epoetin alfa in CKD patients [16,18].

Extended epoetin alfa dosing may provide additional flexibility of dosing, be more convenient for the patient and clinician, and improve patient compliance. Prospective, randomized clinical studies are in progress to explore more fully the efficacy and tolerability of these extended epoetin alfa dosing regimens in patients with anaemia of CKD.



   Acknowledgments
 
The authors wish to acknowledge the contributions of the following individuals to this study (all locations are in the USA): Muralidhar Achaya, MD, Outcomes Research International Inc., Hudson, FL; May Chiu, MD, Diablo Nephrology Medical Group, Walnut Creek, CA; Loren Cohen, MD, Cincinnati, OH; Charles K. Crumb, MD, Southwest Nephrology Associates, Houston, TX; Carol DiRaimondo, MD, Diablo Nephrology Medical Group, Walnut Creek, CA; Victor Gura, MD, Medipace Medical Group, Beverly Hills, CA; Elisha Hatfield, BS, Dallas Nephrology Associates, Dallas, TX; Khalad Nass, MD, Northeast Georgia Diagnostic Clinic, Gainsville, GA; Phylis Neary, RN, Western New England Renal and Transplant Associates, Springfield, MA; Sueanne Petroff, ANP, Western New England Renal and Transplant Associates, Springfield, MA; Jeffrey Posner, MD, Mid Atlantic Nephrology Associates, PA, Baltimore, MD; John Reed, MD, Eastern Nephrology Associates, Greenville, NC; Marcos Rothstein, MD, Barnes Jewish Hospital Dialysis Center, St. Louis, MO; Chris Sholer, MD, Nephrology Consultants, Oklahoma City, OK; and Jonathan Slater, MD, Pioneer Valley Nephrology, Springfield, MA. This study was supported by Ortho Biotech Clinical Affairs, LLC.

Conflict of interest statement. M.G. is a consultant for, receives research grants from, and serves on the Speaker's Bureau for Ortho Biotech Clinical Affairs, LLC. C.V.R. serves as a consultant for and is on the Speaker's Bureau for Roche Pharmaceuticals. S.B. and L.T. own stock in and are employees of Ortho Biotech Clinical Affairs, LLC. M.K. owns stock in and is an employee of Johnson & Johnson Pharmaceutical Research and Development, LLC. M.C. received research grants from and serves on the Speaker's Bureau for Ortho Biotech Clinical Affairs, LLC.



   References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 26.10.04
Accepted in revised form: 28. 4.05





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