Perit Dial Int
29(2):
199-203
2009
© 2009 International Society for Peritoneal Dialysis
SUBCUTANEOUS ADMINISTRATION OF DARBEPOETIN ALFA EFFECTIVELY MAINTAINS HEMOGLOBIN CONCENTRATIONS AT EXTENDED DOSE INTERVALS IN PERITONEAL DIALYSIS PATIENTS
Yu-Wei Fang1 and
Chung-Hsin Chang1,2
Division of Nephrology,1 Department of Internal
Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei; Department of
Medicine,2 School of Medicine, Fu Jen Catholic
University, Taipei County, Taiwan
Correspondence to: C.H. Chang, Division of Nephrology, Department of Internal
Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95, Wen-Chan Road, Shih-Lin,
Taipei 111, Taiwan.
m001091{at}ms.skh.org.tw
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ABSTRACT
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Objective: Darbepoetin alfa is an
erythropoietic-stimulating protein with a threefold longer half-life than
recombinant human erythropoietin (rHuEPO) and can be used less frequently in
the treatment of renal anemia. The purpose of this single-center single-arm
study was to determine whether darbepoetin alfa, when administered at extended
dose intervals, is as effective as rHuEPO for the treatment of renal anemia in
patients on peritoneal dialysis.
Methods: Patients on peritoneal dialysis for at least 3
years receiving stable rHuEPO therapy were shifted to darbepoetin alfa
administered every week, or every other week, using the recommended 200:1
conversion factor. The doses of darbepoetin alfa were titrated to maintain
hemoglobin within ±1.0 g/dL of patients' baseline values and within a
range of 9.0 – 12.0 g/dL for up to 24 weeks (20-week dose titration
period followed by 4-week evaluation period). The primary end point was the
change in hemoglobin levels between baseline and evaluation period.
Results: 73 patients completed the study; mean age was
52.1 years; 30 males. Mean baseline and evaluation period hemoglobin levels
were similar (9.56 ± 1.11 vs 9.73 ± 1.41 g/dL, p =
0.248). Mean rHuEPO dose was 92.9 IU/kg/week (equivalent to 0.46 µg/kg/week
darbepoetin alfa), which was higher than darbepoetin alfa dose during the
evaluation period (0.46 vs 0.34 µg/kg/week, p = 0.038). In
addition, ferritin levels decreased (483 ± 26 vs 396 ± 19 ng/dL,
p = 0.014). The other parameters, such as albumin, C-reactive
protein, transferrin saturation, Kt/V, and weekly creatinine clearance showed
no statistical difference between the two regimens. No serious or major
adverse effects were observed with darbepoetin alfa during the study.
Conclusions: Using lower dosage and frequency,
darbepoetin alfa effectively maintains hemoglobin levels in peritoneal
dialysis patients previously maintained on erythropoietin beta. Similar
effects on hemoglobin can be maintained with even lower levels of ferritin
during darbepoetin alfa use. These results show that darbepoetin alfa is safe,
effective, and convenient in treating renal anemia in peritoneal dialysis
patients.
KEY WORDS: Anemia; darbepoetin alfa; erythropoietin; end-stage renal disease; chronic kidney disease.
It is well-known that recombinant human erythropoietin (rHuEPO) can correct
anemia and improve quality of life in patients with end-stage renal disease
with respect to cardiac function, exercise tolerance, and reduced need for
transfusion
(1–3).
rHuEPO was introduced intravenously when initially administered to dialysis
patients; since 1988, the subcutaneous route for rHuEPO has been known to
lower weekly dosage requirements by 20% – 30% compared with intravenous
administration
(2–4).
This advantage is practical in peritoneal dialysis (PD) and predialysis
patients. The problem remaining in such patients is whether the frequency of
administration can be reduced for convenience and to improve clinical
compliance.
In conventional rHuEPO therapy, such as erythropoietin beta, shorter
half-life makes two or three times per week subcutaneous administration
necessary. This is uncomfortable and inconvenient for stage 3 – 4
chronic kidney disease and PD patients. Darbepoetin alfa is a glycoprotein
with 60% protein and 40% carbohydrate
(5,6).
The serum half-life and biological activity of erythropoietin are dependent on
the sialic acid-containing carbohydrate content. Darbepoetin alfa was designed
by insertion of two N-linked carbohydrate chains into the primary sequence of
rHuEPO to create five N-linked carbohydrate molecules
(7,8).
Due to this increased sialic acid-containing carbohydrate content, darbepoetin
alfa has a three-times longer half-life In vivo compared with rHuEPO
(8), making once weekly or once
every other week dosing feasible in treating renal anemia.
We conducted a study in PD patients that previously maintained hemoglobin
levels with erythropoietin beta. After shifting to darbepoetin alfa, Hb levels
as well as clinical parameters were checked. We compared these data at
baseline and after 24 weeks of darbepoetin alfa administration.
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MATERIALS AND METHODS
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To conduct this study, from December 2003 to December 2004, we collected 82
patients with end-stage renal disease undergoing PD for at least 3 years, on
stable erythropoietin beta therapy, whose Hb levels were maintained between
9.0 and 12.0 g/dL, and that had adequate iron storage. Patients were excluded
if they had a history of blood transfusion, massive blood loss, systemic
infection, malignancy, NYHA class III or IV congestive heart failure, or
uncontrolled hyperparathyroidism in the first 6-month period during the shift
to darbepoetin alfa. Hematological disorders and inflammatory disorders such
as systemic lupus erythematous were also excluded.
Seventy-three patients completed the study and were classified into two
groups according to their primary renal diagnosis as diabetic related or not.
These patients were shifted from erythropoietin beta to darbepoetin alfa
according to the recommended initial conversion formula of 200 IU
erythropoietin beta = 1 µg darbepoetin alfa
(5–7).
Both erythropoietins were prescribed subcutaneously and had the same titration
protocol except for the dosing intervals
(Table 1). Due to the
restrictions of the National Health Insurance program in Taiwan, this dosage
adjustment would maintain Hb levels between 9.0 and 11.0 g/dL. Intravenous and
oral iron supplements were given routinely to maintain serum ferritin over 200
ng/dL and transferrin saturation over 25%, according to the iron profile,
which was checked every 3 months. Oral iron therapy was prescribed in the form
of ferric hydroxide polymaltose complex (100 mg twice daily). Patients were
instructed to take the tablets on an empty stomach and at least 2 hours apart
from phosphate-binder ingestion. Intravenous infusion of iron sucrose (100
– 300 mg diluted in 100 mL normal saline administered for 30 minutes)
was titrated according to the protocol
(Table 2).
After 24 weeks, data including Hb level, iron profile, and other
biochemical parameters were evaluated. In addition, we also compared these
data in each disease group to see if primary renal disease influences the
effect of darbepoetin on Hb level. The study design is presented in
Figure 1.
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Figure 1 — Scheme of the study design. PD = peritoneal dialysis; rHuEPO =
recombinant human erythropoietin.
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STATISTICAL ANALYSIS
All patients included in this study received 24 weeks of subcutaneous
darbepoetin alfa. Baseline data, including Hb level, iron profile, albumin,
and biochemical parameters as well as Kt/V, were collected at the time of
shifting to darbepoetin alfa. Data from evaluation periods included the same
parameters collected after 6 months of darbepoetin alfa administration.
Initial and 6-month data were compared by paired t-test. Statistical
significance was defined as p < 0.05. All statistical analyses
were performed using SPSS software v13.0 (SPSS Inc., Chicago, IL, USA).
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RESULTS
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Of the initial 82 patients recruited, 9 were excluded (6 had a history of
gastrointestinal bleeding and had previously received blood transfusions, and
3 suffered from peritonitis with sepsis); 73 patients remained in this study.
Average age of the remaining 73 patients was 52.1 years. The number of male
patients and female patients was 30 and 43 respectively. There were 31 (42.5%)
patients in the diabetic group and 42 (57.5%) in the nondiabetic group
(Table 3). Baseline Hb level
was 9.56 ± 1.11 g/dL and was maintained at 9.73 ± 1.41 g/dL on
shifting to darbepoetin alfa for 6 months (p = 0.248). Mean Hb levels
over time are displayed in Figure
2. Mean erythropoietin beta dose at baseline was 92.9 IU/kg/week
(equivalent to 0.46 µg/kg/week darbepoetin alfa) and mean darbepoetin alfa
dose during the evaluation period of the study was 0.34 µg/kg/week. This
difference reached statistical significance (p = 0.038)
(Table 4).
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Figure 2 — Mean (±SD) hemoglobin levels over time in 73 patients.
Initial 12 were screening period, followed by administration of darbepoetin
alfa. After titrating for 20 weeks, a 4-week evaluation period was
conducted.
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When taking primary renal disease into consideration, the diabetes-related
group had mean Hb levels of 9.42 ± 1.46 g/dL and 9.67 ± 1.78
g/dL at baseline and after darbepoetin alfa use (p = 0.214)
respectively. In the non diabetes-related group, mean Hb levels were 9.68
± 0.75 g/dL and 9.78 ± 1.01 g/dL respectively (p =
0.622). In the diabetic group, mean erythropoietin beta dose at baseline was
88.1 IU/kg/week (equivalent to 0.44 µg/kg/week darbepoetin alfa) and mean
darbepoetin alfa dose during the evaluation period was 0.35 µg/kg/week.
This difference reached statistical significance (p = 0.027). The
difference between erythropoietin beta dose and darbepoetin alfa dose also
reached statistical significance (p = 0.043) in the nondiabetic
group. In addition, ferritin level was higher at baseline than during the
evaluation period (483 ± 26 vs 396 ± 19 ng/dL, p =
0.014) but transferrin saturation was not different (31.74% ± 2.73% vs
32.70% ± 2.58%, p = 0.732).
Baseline serum albumin, C-reactive protein (CRP), and aluminum levels and
other biochemical parameters were similar to those during the evaluation
period (Table 5). Parameters of
dialysis adequacy, such as Kt/V (2.2 vs 2.1, p = 0.842) and weekly
creatinine clearance (65.01 ± 7.22 vs 66.06 ± 2.03 L/week/1.73
m2, p = 0.207), before and after darbepoetin alfa use were
also similar.
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TABLE 5 Differences in Kt/V, Weekly Creatinine Clearance (WCrCl), and Serum
Biochemical Parameters Before and After Use of Darbepoetin Alfa
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SAFETY
In our study, darbepoetin alfa was well tolerated. Only 16% of patients
reported an adverse event. The most commonly occurring event was hypertension
(13%), followed by myalgia (7%), hypotension (5%), transient injection-site
pain (3%; mostly following the first subcutaneous administration), and
headache (1%). No patient withdrew from the study due to adverse effects of
darbepoetin alfa.
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DISCUSSION
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Previous randomized studies have examined the effects of switching from
rHuEPO to darbepoetin alfa in patients with chronic renal insufficiency
(9) and requiring hemodialysis
(10–14).
However, a few studies examined the effect of darbepoetin alfa in small
numbers of PD patients
(12,13,15).
The results of the present study further demonstrate that, using lower dosage
and frequency, darbepoetin alfa can effectively maintain Hb levels in PD
patients previously maintained on erythropoietin beta. Mean Hb levels were
maintained above 9 g/dL throughout the study period. Although the recommended
level of Hb is 11 – 12 g/dL according to international guidelines, due
to the limitation of National Health Insurance payments in Taiwan, the target
Hb of erythropoietin use in PD patients in Taiwan is up to 11 g/dL; this is
why mean Hb levels in our patients were around 9.5 – 10.0 g/dL. Since
target Hb levels before and after shifting to darbepoetin alfa did not change,
we considered whether the efficacies of these two erythropoietins were
comparable.
The statistically insignificant difference in Hb levels between baseline
and evaluation periods revealed the same effectiveness of these two agents.
However, the significant difference in dosage between the two agents shows the
superior potency of darbepoetin alfa over erythropoietin beta. This means that
similar Hb levels can be maintained with lower dosage of darbepoetin alfa.
When we divided our patients into diabetic and nondiabetic groups, mean Hb
levels after darbepoetin alfa use did not differ from baseline data for either
group. The advantage of lower dosage of darbepoetin alfa did not seem to
differ between diabetic and nondiabetic groups, showing that the primary renal
disease plays only a limited role in the effectiveness of darbepoetin. In
addition, the similar levels of serum albumin, CRP, aluminum, and other
biochemical parameters, as well as Kt/V and weekly creatinine clearance,
indicate the stable condition of our patients throughout the study period.
This allowed comparison of the effectiveness of these two agents on Hb level
without interference by other clinical situations.
In addition, when iron profile was taken into consideration, significantly
lower ferritin concentrations were noted during the evaluation period. This
revealed that similar levels of Hb could be maintained with even lower
concentrations of ferritin during the period of darbepoetin alfa use. Although
ferritin is an acute-phase protein that might be affected by inflammation
status, there was no change in CRP levels after shifting to darbepoetin alfa;
therefore, a decrease in ferritin due to change in inflammation status was
unlikely. This phenomenon may show that either the potency of darbepoetin alfa
is less affected by iron status than erythropoietin beta, or that darbepoetin
alfa is more potent independent of iron status; this hypothesis needs further
study for clarification.
We used darbepoetin alfa 20 µg once every other week when patients' Hb
levels were between 10.0 and 11.0 g/dL. No difference in Hb was seen when the
administration interval was prolonged. In the study by Grzeszczak et
al. (16), epoetin beta,
subcutaneously, once weekly, was as effective as once every 2 weeks in PD
patients. Carrera et al.
(17) also reported that once
every other week administration of intravenous darbepoetin alfa is as
effective as once per week administration in dialysis patients. There was no
obvious effect of the two dosage intervals in our study; this indicates that
every other week administration via the subcutaneous route may also be
feasible in patients on PD.
In conclusion, this study indicates that Hb levels can be effectively and
safely maintained with darbepoetin alfa, at reduced dosage and frequency, in
PD patients. Reduced dosing frequency can minimize the number of injections
and so offers significant advantages for both patients and healthcare workers.
The effect of subcutaneous darbepoetin on Hb is similar to erythropoietin
beta, even with lower iron storage. Therefore, subcutaneous darbepoetin alfa
administration should be considered in treating renal anemia in patients on
PD.
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DISCLOSURE
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No financial conflict of interest to declare.
Received 22 December 2007;
accepted 8 July 2008.
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ABSTRACT
MATERIALS AND METHODS
