|Year : 2016 | Volume
| Issue : 6 | Page : 1182-1187
|Initiation of darbepoetin for management of anemia in non-dialysis-dependent patients with chronic kidney disease
Fatma Al Raisi1, Issa Al Salmi2, Pramod Kamble2, Muna Al Shehri1, Faissal A. M. Shaheen3
1 Department of Pharmacy, The Royal Hospital, Muscat, Oman, Oman
2 Department of Renal Medicine, The Royal Hospital, Muscat, Oman
3 Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia
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|Date of Web Publication||28-Nov-2016|
| Abstract|| |
The anemia of chronic kidney disease (CKD) is a common comorbidity seen in kidney diseases. It is also associated with increased cardiovascular morbidity and mortality and diminished quality of life. Often, patients with CKD of different stages require erythropoiesis-stimulating agents (ESAs) to maintain their hemoglobin (Hb) within the target range. Darbepoetin alfa is a newer ESA with a longer half-life than recombinant human erythropoietin (EPO). The objective of this study is to assess the efficacy and safety profile of twice-monthly (Q2W) and once a month (1QM) darbepoetin alfa in CKD patients, not on dialysis. The secondary objective was to assess the appropriate dose conversion from EPO to darbepoetin. Patients with CKD not on dialysis, receiving darbepoetin alfa every other week, or once every month, and with stable Hb levels between 10 and 12 g/dL, were enrolled in this single-center, open-label, single-arm study. In this study, 36 patients (21 female, 15 male) were enrolled with a mean age of 46.4 ± 20.12 years. About 56% of the patients (n = 20) received darbepoetin alfa 40 μg Q2W for more than three months and 36% (n = 13) were on once-monthly doses, whereas the other 8% (n = 3) were on variable doses ranging from 20 to 60 μg every two weeks. More than 80% of the patients were converted from short-acting EPO to darbepoetin corresponding to a conversion ratio of 672.2 IU:1 μg (standard deviation = 488.5). Hb levels ≥10 g/dL were maintained in 77.78% of the patients. The safety profile of darbepoetin alfa in this study was recorded, and no significant adverse effects were noted. Our study suggests that darbepoetin alfa, administered in fixed small doses and frequency of Q2W or Q1M, maintained Hb levels ≥10 g/dL in patients with CKD, not on dialysis.
|How to cite this article:|
Al Raisi F, Al Salmi I, Kamble P, Al Shehri M, Shaheen FA. Initiation of darbepoetin for management of anemia in non-dialysis-dependent patients with chronic kidney disease. Saudi J Kidney Dis Transpl 2016;27:1182-7
|How to cite this URL:|
Al Raisi F, Al Salmi I, Kamble P, Al Shehri M, Shaheen FA. Initiation of darbepoetin for management of anemia in non-dialysis-dependent patients with chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Jan 19];27:1182-7. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1182/194607
| Introduction|| |
Anemia of chronic kidney disease (CKD) is a common comorbidity associated with kidney diseases; the prevalence of which increases with increased duration of the disease and number of hospitalizations. ,,, Anemia is related to increased cardiovascular morbidity and mortality and diminished quality of life in these patients. , Erythropoiesis-stimulating agents (ESAs) have caused improvement in the patient outcomes and quality of life. Recent research has resulted in the development of a long-acting erythropoietin (EPO); darbepoetin alfa which is a newer erythropoietic protein and has a longer half-life than recombinant human EPO.  It is known to be an effective alternative in treating anemia in patients with non-dialysis-dependent CKD with extended dosing interval of once every two weeks or even once a month in patients with CKD and anemia.  This regimen is more convenient for administration by health-care providers and patients.
The optimal starting weekly dose of darbepoetin is 0.45-0.75 μg/kg body weight. Dosing remains the same for both the subcutaneous (SC) and intravenous (i.v.) routes of administration. 
Darbepoetin was recently approved by the Central Drug Committee at the Ministry of Health in Oman to be included in the national formulary for non-dialysis-dependent CKD patients.
The use of darbepoetin in patients being treated with conventional EPO requires dose conversion. , The current conversion table provided by the darbepoetin manufacturers was not followed for the patients before the start of this study;  however, starting doses were fixed at a small dose of 40 μg, and then the doses were modified according to the hemoglobin (Hb) levels. The primary aim of this study was to examine the efficacy and safety profile of twice-monthly (Q2W) and once monthly (Q1M) darbepoetin alfa in nondialysis-dependent CKD patients. The secondary objective was to assess the appropriate dose conversion from EPO to darbepoetin in these patients.
| Materials and Methods|| |
This is an open-label, single-center, cohort, retrospective study. The study was conducted at the Nephrology Department of the Royal Hospital, the largest Governmental Tertiary Care Hospital in Oman having more than 850 beds. All adult patients with anemia associated with CKD, on darbepoetin for more than three months, were included in the study. Ethical approval was obtained from the Research Committee at the Royal Hospital. Patients with CKD but not on dialysis, receiving darbepoetin alfa every other week (Q2W) or once monthly (Q1M), were enrolled in the study. Patients' profiles in the hospital electronic system (Al-Shifa) were reviewed, and all required data were filled in a pre-designed data collection form. All relevant baseline laboratory parameters were recorded at the start of treatment including creatinine clearance, body mass index (BMI), serum calcium, phosphate, parathyroid hormone (PTH), ferritin, and transferrin saturation (TSAT). The Hb level was recorded at the start, one month and three months after starting darbepoetin. Darbepoetin doses were not changed during the study period.
| Results|| |
A total of 36 patients (21 female, 15 male) were enrolled; their mean age was 46.5 years (standard deviation [SD] = 20.1). The etiology of kidney disease in most of the patients was hypertension (24.67%) and diabetes (11.31%), followed by focal and segmental glomerulosclerosis (5.14%) and other autoimmune disorders (4.1%, [Figure 1]). More than half the patients (55.5%) were in CKD Stage 5 according to the KDIGO CKD classification, whereas patients with CKD Stages 4 and 3 were seen in 38.8% and 5.7% of patients, respectively. The estimated glomerular filtration rate (eGFR) of the study patients was calculated, and the mean eGFR was 17.25 mL/min/1.73 m 2 (SD = 9.92, [Table 1]). All other parameters including TSAT, ferritin, serum calcium, phosphate, and PTH that were measured for the patients enrolled in the study are listed in [Table 1]. Mean blood pressure (BP) was stable within the target range during the study period.
The average Hb level at start of therapy was 9.16 g/dL (SD = 1.44) and after three months, it was 10.79 g/dL (SD = 1.44, [Figure 2]); there was a mean increase of 1.65 g/dL in the Hb level [Table 1]. The Hb was maintained at >10 g/dL in 28 patients (77.8%), of whom, two (7%) had Hb level >12g/dL requiring reducetion of darbepoetin dose. On the other hand, eight patients (22.2%) had Hb level <10 g/dL despite being on darbepoetin treatment for 12 weeks.
All patients were on polypharmacy with an average of 5.2 drugs per prescription (SD = 0.97) and received darbepoetin alfa either Q2W or Q1M for more than three months with an average dose per week of 15.9 μg (SD = 5.55). About 56% of the patients (n = 20) received darbepoetin alfa 40 μg (Q2W) for more than three months and 36% (n = 13) were on once-monthly doses, whereas the other 8% (n = 3) were on variable doses ranging from 20 to 60 μg every two weeks.
About 89% of the patients were converted from short-acting EPO to darbepoetin, whereas 11% of the patients had no previous exposure to EPO. The mean dose of EPO before the start of the study was 11.125 IU/week (SD = 3603.38) SC. The conversion ratio of EPO to darbepoetin at initiation of darbepoetin was supposed to be 200 IU:1 μg according to the manufacturer's recommendations; however, the doses were modified to maintain Hb within the target range in these patients to an increased conversion ratio of 672.2 IU:1 μg (SD = 488.5) and no dose modification took place during the study period. However, suggestion for dose modification according to patient's Hb level was given to the treating physicians by the clinical pharmacist after completion of data collection. The safety profile of darbepoetin alfa in this study was recorded, and no significant adverse effects were observed to the treatment regimen; nevertheless, patients were satisfied with the reduction in frequency of injections from thrice a week to once every two weeks or even once a month.
| Discussion|| |
Our study showed that non-dialysis CKD patients with mean eGFR of 17.25 mL/min/1.73 m 2 (SD = 9.92) were receiving polypharmacy (average of 5.2 drugs); darbepoetin therapy helped in maintaining Hb above 10 g/dL with a mean raise of 1.65 g/dL over three months; the Hb was maintained at >10 g/dL in 77.8% of the patients.
Our study included all patients on darbepoetin for more than three months, which is an acceptable time to estimate the effectiveness of treatment. The Hb level was maintained within the desired target levels in 72% of the patients despite being on very small doses of darbepoetin compared to doses used in other studies.
In a study conducted in Saudi Arabia by Shaheen et al, it was recorded that a conversion ratio of 200 IU:1 μg might be an overestimate, and they recommended a ratio of 361 IU:1 μg, and in some patients, the ratio used was as low as 450 IU:1 μg.  In another study by Jones et al, they showed that in some patients, small doses of darbepoetin were used with a conversion ratio of 450 IU:1 μg with significant outcomes.  A study conducted among Japanese dialysis patients in whom the ESA was changed from EPO to darbepoetin concluded that the conversion ratio of 350.5 IU:1 μg was an effective option to maintain Hb within the target range. 
A randomized controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients by Nissenson et al aimed to determine whether darbepoetin alfa is as effective as EPO for the treatment of anemia when administered at a reduced dosing frequency.  The trial included 338 patients who continued to receive EPO therapy administered i.v. three times weekly, and on the other arm, 169 patients who were changed to darbepoetin alfa administered i.v. once weekly.  The study concluded that darbepoetin alfa maintained Hb levels as effectively and safely as EPO in patients with CKD and with a reduced dosing frequency. 
The dose used in our patients was even lower than the above-mentioned studies at a ratio of 672.2 IU:1 μg, which may be explained by the intra-variable difference among different ethnic groups which impacts the response to different dose regimens. However, this requires further investigation to be able to justify the differences in conversion ratios from EPO to darbepoetin in different populations.
The reduced doses used in our study may contribute positively in cost saving over time and might even be appropriate to be considered in patients on peritoneal dialysis.
Anemia of CKD requires vigilant therapy to be able to keep the patients in target Hb levels according to clinical practice guidelines without adverse effects such as rise in Hb levels above the target range or elevations in BP. ,, There were no reported adverse drug reactions to darbepoetin therapy in our patients during the study period, and it might be because of the small dose of the drug used; similar experience has been reported in many other studies. ,,
Even though our study period was short, it seems that darbepoetin in doses as small as 40 μg every two weeks or 80 μg once a month is a safe and effective option for the treatment of non-dialysis CKD-associated anemia, and the safety profile of darbepoetin is similar to that of EPO according to the experience of many published studies. ,,
| Limitations|| |
Our study had some limitations: There was limited experience with the drug, and the duration of the study was short. Moreover, the study was an open label and uncontrolled one, with a small number of patients.
| Conclusions|| |
Darbepoetin alfa administered Q2W or Q1M maintained Hb levels >10 g/dL in patients with non-dialysis-dependent CKD. This treatment regimen may help optimize anemia management in CKD patients with reduced frequency of injections, which will enhance compliance, thus improving patient outcomes and quality of life. ,,,,, Further studies are needed to determine whether this reduction in darbepoetin dose and reduced frequency will result in improved anemia management in non-dialysisdependent patients.
Conflict of interest: None declared.
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Issa Al Salmi
Department of Renal Medicine, The Royal Hospital, 23rd July Street, P. O. Box 1331, Code 111, Muscat
[Figure 1], [Figure 2]
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