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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 3  |  Page : 365-372
Darbepoetin Use for the Treatment of Anemia in Hemodialysis Patients in Saudi Arabia


1 Department of Nephrology in King Fahad Hospital, Jeddah, Saudi Arabia
2 Department of Nephrology, King Abdulaziz and Oncology Center, Jeddah, Saudi Arabia
3 Department of Nephrology, Security Forces Hospital, Riyadh, Saudi Arabia
4 Department of Nephrology, King Khaled University Hospital, Riyadh, Saudi Arabia
5 Department of Nephrology, Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia

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   Abstract 

Erythropoietin replacing proteins have improved patient outcomes and quality of life. Darbepoetin has a 3-fold longer half-life than recombinant human erythropoietin (rHuEPO). In this study, we investigate the efficacy and safety of the conversion of stable hemodialysis patients from the current short-acting r-HuEPO (EPO alfa or beta) to the long-acting darbepoetin. In addition, we verified the appropriateness of the current ratio of conversion of the short acting to the long-acting erythropoietin in an open label prospective multi-center study. The study design included 12 weeks darbepoetin administration. The conversion ratio was 200 IU of short acting r-HuEPO to 1 microgram of darbepoetin. We adjusted the dose of darbepoetin to maintain hemoglobin levels between 110-120 g/L. There were 33 patients who satisfied the entry criteria. The study was conducted from January-June, 2005. The study patients included 18 men and 15 women, the mean age was 50.4 ± 12.3 years and the mean duration on HD was 323 ± 51.9 days. There was a significant decrease in the mean dose of darbepoetin from 37.3 ± 12.9 ug/week at week 1 of the study to 20.8 ± 16.6 ug/week by the end of week 12 (p< 0.00003) while the hemoglobin level was maintained within the previously defined range. The initial conversion ratio from short-acting erythropoietin to darbepoetin was 200 IU to 1 microgram. However, at the end of week 12, the mean dose of darbepoetin decreased to an equivalent conversion ratio to 361 IU: 1 microgram. This may reflect great savings in the cost of treatment. Our experience with darbepoetin reveals that darbepoetin is effective and safe for the treatment of anemia in hemodialysis patients and has a more convenient dosing schedule than short-acting erythropoietin. The darbepoetin dosage decreases over time and savings are expected to greater with darbepoetin more than with short-acting erythropoietin with time.

Keywords: Erythropoietin, Renal, Hemodialysis, Cost, Darbepoetin, Saudi, Anemia.

How to cite this article:
Shaheen FA, Akeel N, Alfi A, Harbi A, Tarif N, Souqiyyeh MZ. Darbepoetin Use for the Treatment of Anemia in Hemodialysis Patients in Saudi Arabia. Saudi J Kidney Dis Transpl 2006;17:365-72

How to cite this URL:
Shaheen FA, Akeel N, Alfi A, Harbi A, Tarif N, Souqiyyeh MZ. Darbepoetin Use for the Treatment of Anemia in Hemodialysis Patients in Saudi Arabia. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2020 Feb 22];17:365-72. Available from: http://www.sjkdt.org/text.asp?2006/17/3/365/35769

   Introduction Top


Erythropoietin replacing proteins have improved patient outcomes and quality of life. Recent research has resulted in the develop­ment of a long-acting erythropoietin, darbepoetin, which is more convenient for administration by physicians and patients.

Darbepoetin alfa is a new hyperglycosylated recombinant erythropoietin protein with a 3-fold longer half-life than recombinant human erythropoietin (rHuEPO). Darbepoetin alfa administered intravenously (i.v.) once weekly or once every other week is an effective treatment regimen for hemodialysis or PD patients with renal anemia.[1],[2],[3] For patients who continued treatment of darbepoetin up to 52 weeks, hemoglobin (Hgb) was maintained between 100 and 130 g/L from mean baseline values of 84 and 87 g/L and the optimal weekly starting dose was 0.45-0.75 ug/kg. [4] Dosing is possible for both the sub­cutaneous (s.c.) and i.v. routes of administration in hemodialysis patients and the i.v. route is even more efficient relative to the short­acting erythropoietin.[5]

Furthermore, darbepoetin has been proven to be effective in maintaining Hgb levels in CKD patients with a s.c. monthly dosing schedule.[6]

The use of darbepoetin in existing patients treated with rHuEPO requires conversion dosing. The current conversion table may underestimate the dose.[7]

A therapeutic interchange program to convert therapy for all inpatients under­going dialysis from erythropoietin alfa to darbepoetin alfa for treatment of chronic kidney disease-related anemia has been implemented and resulted in cost-savings in Europe and USA.[8],[9],[10],[11],[12],[13],[14],[15]

Our primary aim in this study was to establish the efficacy and safety of the darbepoetin conversion of stable hemodialysis patients from the current short-acting r-HuEPO (EPO alfa or beta) to the long-acting darbe­poetin. Our secondary aim was to check the appropriateness of the current ratio of conversion of the short acting to the long acting erythropoietin.


   Methods and Patients Top


This is an open label prospective multi-center study including the following hospitals: King Fahed Hospital, Jeddah, King Abdulaziz and Oncology Center, Jeddah, Security Forces hospital, Riyadh, and King Khaled University Hospital, Riyadh, Saudi Arabia. The study was conducted between January -June, 2005.

Included in the study were patients who were maintained on chronic hemodialysis for at least 3 months prior to initiating darbepoetin. They were optimally dialyzed as judged by usual dialysis and serum chemistry parameters (KT/V: >1.1) The patients' pre­study hemoglobin levels ranged from 110­120 g/L. All the patients were maintained on stable doses of erythropoietin administered subcutaneously for at least 8 weeks prior to commencement of the study (< 25% change of dose). The patients had no other causes of anemia other than chronic renal failure or evidence of folate, vitamin B12, or iron deficiency. There was no evidence of relevant liver disease, severe secondary hyperpara­thyroidism (>1500 pg/ml (148 pmol/L over the last 12 months) severe cardiac disease, chronic pulmonary disease associated with functional limitation, malignancy, major organ transplantation or other severe illnesses. All female patients had a negative pregnancy test and were not pregnant or breast-feeding at the time of entry into the study. The patients were not taking drugs that could affect erythropoiesis (e.g. androgens).

The patients had no blood transfusions during the 8 weeks prior to enrollment. Each patient signed an informed consent and had a comprehensive history and physical exam at the beginning and end of the study. The patients continued the same medications they were taking prior to the beginning of the study including antihypertensives and iron supplements.

Lab investigations, which included complete blood count and differential, renal function tests (Urea, creatinine, KT/V urea, electrolytes, calcium, phosphate), liver function tests (total proteins, albumin, liver enzymes, cholesterol and alkaline. phosphatase), iron stores tests (iron, ferritin, iron binding capacity, transferrin saturation), parathyroid hormone level and glucose, were performed at entry, every 4 weeks and at the end of the study.

The study design included 12 weeks of darbepoetin (Aranesp ®, Amgen, USA) at a dose calculated according to the weekly cumulative dose of the short-acting EPO at the time of pre-study assessment visit.

The conversion ratio was 200 IU of short acting r-HuEPO to 1 microgram of darbepoetin. The administration of darbepoetin was i.v. or s.c. using the available pre-filled syringes of 20, 30, 40, 50, and 60 /µg. The dose was adjusted to maintain hemoglobin levels between 110-120 g/L. Complete blood count tests were performed on a weekly basis to monitor hemoglobin levels.

The dose of darbepoetin was increased or decreased by 25% to maintain the hemoglobin level within the set limits on two consecutive Hgb readings. If the highest was surpassed the dose of dar bepoetin was then decreased followed by a reduction in the frequency of dosing.

We followed the safety of darbepoetin that included the nature, frequency, severity, relation to treatment, and outcome of adverse events including the use of antihypertensive medi­cations, IV iron medications, and access related events. Incidence of all adverse events (including serious adverse events) reported by the investigators as related to the study drug would be documented.


   Statistical Analysis Top


We expressed the results of the age, mean blood pressure (1/3 systolic+2/3 diastolic), hemoglobin levels and doses of the darbepoetin as mean ± standard deviation. Continuous data were analyzed using an independent-sample t test. We compared the means and set the significance level to p<0.05.


   Results Top


There were 33 patients who satisfied the entry criteria. There were 20 patients enrolled from King Fahed Hospital, Jeddah; six from King Abdulaziz and Oncology Center, Jeddah; four Security Forces hospital, Riyadh; three from King Khaled University Hospital, Riyadh, Saudi Arabia.

The study patients included 18 men and 15 women, the mean age was 50.4 ± 12.3 years and the mean duration on HD was 323 ± 51.9 days. The etiology of renal disease was diabetes mellitus in 11(33%) patients, hyper­tensive nephropathy in 9 (27%), glomerulo­nephropathy in two (6%), vesico-ureteral reflux VUR one (3%), and unknown etiology in 10 (30%). The mean dose of short acting erythropoietin before the start of start of the study was 7454 ± 2570 IU/ week s.c. with a mean dosing frequency of 2.6 times/ week, and the mean hemoglobin level was 115.5 ± 3.6 before the start of the study. The clinical and laboratory parameters were compatible with adequate iron stores, reasonable mineral and bone management and adequate dialysis at baseline, while there was a significant decrease in mean serum iron levels and transferrin saturation at the end of the study, which was expected due to requirement of iron with the continued use of erythropoiesis stimulating agents [Table - 1].

Two (6%) patients discontinued the study: The first patient (aged 48) with renal disease of unknown etiology had a cerebrovascular accident (CVA) at week 10. The second patient (age 56) with diabetic nephropathy developed pulmonary edema at week 8. Both patients had controlled blood pressures at the time of the events. No significant adverse reactions were reported during the study period in the rest of the patients.

Oral iron therapy was continued in 50% of the patients and i.v. iron supplementation in 11% of patients; none of the patients needed blood transfusions during the study period.

[Figure - 1] shows the relationship between hemoglobin levels and the administered doses of darbepoetin. The mean hemoglobin levels remained within the pre-determined range with a significant increase towards the upper limit at the end of week 12 relative to week 1 (p<0.0001). Simultaneously, there was a significant decrease in the mean dose of darbepoetin from 37.3 ± 12.9 µg/week at week 1 of the study to 20.8 ± 16.6 µg/ week at the end of week 12 (p< 0.00003). In 31 (93%) patients, the darbepoetin was administered i.v.

[Figure - 2] shows the averages of the mean blood pressures of the study patients. There was no significant change in blood pressure during the study period. There was also no change in the antihypertensive regimens during the study period in any of the study patients.

We also found that 5 (15%) patients who started with significantly high doses of darbepoetin at the start of the study (equal 10000 IU or more of short-acting erythropoietin) required mean doses comparable to the 28 (85%) patients with lower doses at the end of the study, [Figure - 3]. Furthermore, the patients with high initial doses of darbepoetin in­creased their serum hemoglobin levels more than the group with the low starting dose by the end of the 12 weeks, p<0.0001, [Figure - 4].

The mean initial dose of darbepoetin of 37.3 ± 12.9 µg/week at week 1 of the study was equivalent to a conversion ratio from short-acting erythropoietin to darbepoetin of 200 IU to 1 microgram. On the other hand, at the end of week 12, the mean dose of darbepoetin decreased to 20.8 ± 16.6 µg/week which is equivalent to a conversion ratio of 361 IU: 1 microgram. Furthermore, the subgroup of patients from one center (20 patients) was given a mean dose of 38 ± 7.5 µg/week at week 1 of the study. The dose decreased significantly to 14.8 ± 13.8 µg/week by the 12 th week of darbepoetin administration. Darbepoetin had to be administered every other week in 13/20 (60%) patients to maintain the hemoglobin levels in the maintenance range. This increased the estimated conversion ratio to 400-500 IU:1 microgram, which would have been more appropriate as an initial conversion ratio in our study patients.

There were 13 (40%) HCV+ patients and 20(60%) HCV- patients in our study. We found no significant differences in the mean doses of darbepoetin or mean hemoglobin levels between the two groups over the 12 weeks of the study. None of the patients were on HCV antiviral therapy during the study period.


   Discussion Top


The patients selected in this study had stable hemoglobin levels with stable doses of short-acting erythropoietin. This ensured that the patients did not have resistance to the short-acting erythropoietin secondary to iron deficiency, inflammation, inadequate dialysis or uncontrolled hyperparathyroidism. The measured clinical and laboratory parameters in our cohort further ascertained the uni­formity of the selection.

The results of our short-term study revealed that hemoglobin levels could be maintained by darbepoetin throughout the study period. All the patients were on s.c. dosing of short­acting erythropoietin prior to conversion. There was a steady decline in the doses of darbepoetin toward the end of the study despite the i.v. route of administration in almost all the patients. Our results are compatible with those of Weiss et al. [16] and Locatelli et al. [1],[17] Furthermore, the patients with unusually high initial doses of darbe­poetin profited most from the decrease of the darbepoetin dose during the study period. This was also the experience of other studies. [18]

The adverse effects were minimal in the study patients. The blood pressure did not need further management during the study period. This also was the experience of others. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19]

The two study dropouts were not related to the drug administration since both did not show any thrombotic events during dialysis and had stable blood pressure levels during the study period.

We found that the conversion ratio of erythro­poietin to darbepoetin of 200 IU: 1 microgram at the time of conversion may be an over-estimate. A ratio of 361 IU: 1 microgram could maintain the hemoglobin within the recom­mended limits in our study patients; in some patients, the ratio may even be as low 450 IU: 1 microgram. Others recommended similar ratios.[20],[21]

Finally, there was no association of HCV infection and the efficacy of darbepoetin on the hemoglobin levels during our study. Some studies reported similar results of great benefit of darbepoetin even during anti-HCV therapy.[22],[23],[24],[25],[26]

We conclude that the Saudi experience with Darbepoetin reveals that this long­ acting erythropoiesis stimulating agent is effective and safe for the treatment of anemia in patients on hemodialysis. It is more con­venient for dosing than short-acting erythro­poietin. Predialysis stages of chronic kidney disease and peritoneal dialysis patients may benefit even more from the extended periods between doses. There is a decrease in the dose over time and savings are expected with darbepoetin over time relative to short acting erythropoietin.

 
   References Top

1.Locatelli F, Canaud B, Giacardy F, Martin­Malo A, Baker N, Wilson J. Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo). Nephrol Dial Transplant 2003;18(2):362-9.  Back to cited text no. 1    
2.Martinez Castelao A, Reyes A, Valdes F, et al. Multicenter study of darbepoetin alfa in the treatment of anemia secondary to chronic renal insufficiency on dialysis. Nefrologia 2003;23(2):114-24.  Back to cited text no. 2    
3.Scott SD. Dose conversion from recombinant human erythropoietin to darbepoetin alfa: recommendations from clinical studies. Pharmacotherapy. 2002;22(9 Pt 2):160S-5S.  Back to cited text no. 3    
4.Macdougall IC, Matcham J, Gray SJ; NESP 960245/246 Study Group.Correction of anaemia with darbepoetin alfa in patients with chronic kidney disease receiving dialysis. Nephrol Dial Transplant 2003; 18(3):576-81.  Back to cited text no. 4    
5.Aarup M, Bryndum J, Dieperink H, Joffe P. Clinical implications of converting stable haemodialysis patients from subcutaneous to intravenous administration of darbepoetin alfa. Nephrol Dial Transplant 2006;21(5): 1312-6.  Back to cited text no. 5    
6.Jadoul M, Vanrenterghem Y, Foret M, Walker R, Gray SJ. Darbepoetin alfa admini­stered once monthly maintains haemoglobin levels in stable dialysis patients. Nephrol Dial Transplant 2004;19(4):898-903.  Back to cited text no. 6    
7.Capelli JP, Kushner H. Developing an algorithm to convert erythropoietin dosing to darbepoetin alfa. Nephrol News Issues 2006;20(3):33,35,39.  Back to cited text no. 7    
8.Brophy DF, Ripley EB, Kockler DR, Lee S, Proeschel LA. Darbepoetin alfa therapeutic interchange protocol for anemia in dialysis. Ann Pharmacother 2005;39(11):1808-11.  Back to cited text no. 8    
9.Shalansky K, Jastrzebski J.Complete switch to darbepoetin in a hemodialysis unit. Clin Nephrol 2005;64(1):55-63.  Back to cited text no. 9    
10.Tolman C, Richardson D, Bartlett C, Will E. Structured conversion from thrice weekly to weekly erythropoietic regimens using a computerized decision-support system: a randomized clinical study. J Am Soc Nephrol 2005;16(5):1463-70.  Back to cited text no. 10    
11.Roger SD, Cooper B.What is the practical conversion dose when changing from epoetin alfa to darbepoetin outside of clinical trials? Nephrology 2004;9(4):223-­8.  Back to cited text no. 11    
12.Del Vecchio L, Villa G, Carraro G, et al. Italian study on the treatment of anaemia in chronic dialysis patients switched over to less frequent doses of darbepoetin from human recombinant erythropoietin (rHuEPO). G Ital Nefrol 2004;21(3):259-66.  Back to cited text no. 12    
13.Brunkhorst R, Bommer J, Braun J, et al. Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients. Nephrol Dial Transplant 2004;19(5):1224-30.  Back to cited text no. 13    
14.Molina M, Garcia Hernandez MA, Navarro MJ, De Gracia MC, Ortuno T. Change of EPO treatment from subcutaneous epoetin to intravenous epoetin or darbepoetin alpha. Nefrologia 2004;24(6):564-71.  Back to cited text no. 14    
15.Barnett AL, Cremieux PY. Dose conversion from epoetin alfa to darbepoetin alfa for patients with chronic kidney disease receiving hemodialysis. Pharmacotherapy 2003;23(5):690-3; discussion 693-4.  Back to cited text no. 15    
16.Weiss LG, Clyne N, Divino Fihlho J, Frisenette-Fich C, Kurkus J, Svensson B. The efficacy of once weekly compared with two or three times weekly subcutaneous epoetin beta: Re sults from a randomized controlled multicentre trial. Swedish Study Group. Nephrol Dial Transplant 2000;15: 2014-9.  Back to cited text no. 16    
17.Locatelli F, Baldamus CA, Villa G, Ganea A, Martin de Francisco AL. Once-weekly com­pared with three-times- weekly subcutaneous epoetin beta: Results from a randomized, multicenter, therapeutic-equivalence study. Am J Kidney Dis 2002;40:119-25.  Back to cited text no. 17    
18.Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill-current clinical practice in the United States. Crit Care Med 2004;32:39-52.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Vanrenterghem Y, Barany P, Mann JF, et al. Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with rHuEPO in dialysis patients. Kidney Int 2002;62:2167-75.  Back to cited text no. 19    
20.Jones CH, Ridley L, Richardson D. Which EPO dose perweek? Nephrol Dial Transplant 2002;17:1855.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Rice TL, Castelli EE, Culley CM, Guttendorf S, Skledar SJ. Financial impact of a formulary therapeutic interchange program of darbepoetin alfa (DARBE) for recombinant human erythropoietin alfa (rHuEPO) [abstract P-85D]. Presented at: American Society of Health-System Pharmacists Summer Meeting; June 21-23, 2004; Las Vegas, NV.  Back to cited text no. 21    
22.Spiegel BM, Chen K, Chiou CF, Robbins S, Younossi ZM. Erythropoietic growth factors for treatment-induced anemia in hepatitis C: a cost-effectiveness analysis. Clin Gastroenterol Hepatol 2005;3(10):1034-42.  Back to cited text no. 22    
23.Stravitz RT, Chung H, Sterling RK, et al. Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C. Am J Gastroenterol 2005;100(6):1415-9.  Back to cited text no. 23    
24.Collantes RS, Younossi ZM.The use of growth factors to manage the hematologic side effects of PEG-interferon alfa and ribavirin. J Clin Gastroenterol 2005;39(1 Suppl):S9-13.  Back to cited text no. 24    
25.Mulhall BP, Younossi Z. Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C. J Clin Gastroenterol 2005;39(1 Suppl):S23-7.  Back to cited text no. 25    
26.Ong JP, Younossi ZM. Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia. Cleve Clin J Med 2004;71 Suppl 3:S17-21.  Back to cited text no. 26  [PUBMED]  

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Correspondence Address:
Faissal A.M Shaheen
Jeddah Kidney Center, King Fahad Hospital, P.O. Box 11076, Jeddah 21453
Saudi Arabia
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