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Epoetin Alfa

A Review of its Clinical Efficacy in the Management of Anaemia Associated With Renal Failure and Chronic Disease and its Use in Surgical Patients

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Summary

Synopsis

Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients.

Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemo-dynamics adversely or to precipitate the onset of end-stage renal failure.

Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery.

Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects.

Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion. Limited data indicate improved haematocrit and haemoglobin levels in patients with anaemia of RA who have received epoetin alfa. These observations, together with the significant improvements in quality of life seen in patients with chronic renal failure or cancer who have received the drug, confirm the importance of epoetin alfa as a major advance in the management of anaemia in chronic renal failure and other conditions commonly associated with aging.

Overview of Pharmacodynamic Properties

Epoetin alfa increases reticulocyte counts and raises haematocrit and haemoglobin levels by stimulating the proliferation, differentiation and maturation of erythroid progenitor cells. Platelet and monocyte counts may also increase, but remain within normal limits. A number of changes in cardiovascular parameters, including increased mean arterial pressure and total peripheral resistance, and reduced cardiac output, have been noted in patients with chronic renal failure (CRF) who have received the drug. Results of studies on platelet and fibrinolytic effects of epoetin alfa have been inconclusive to date.

Overview of Pharmacokinetic Properties

The pharmacokinetic properties of epoetin alfa are similar in healthy volunteers and patients with CRF. Animal studies suggest that the drug is distributed mainly to the liver and kidneys, with specific uptake into the bone marrow. Dose-proportional increases in plasma concentrations of epoetin alfa are observed after either intravenous or subcutaneous administration; lower peak plasma concentrations are achieved with the latter route, but plasma elimination half-life is extended (≤25 hours, compared with ≤7.9 hours after intravenous administration). The volume of distribution of the drug equates to plasma volume, and elimination occurs in a monoexponential fashion via predominantly nonrenal mechanisms.

Therapeutic Use

Most of the clinical studies of epoetin alfa have been carried out in patients with CRF requiring haemodialysis or peritoneal dialysis, and consistently showed the drug to increase haemoglobin levels (by 26 to 75% over baseline), raise haematocrit (by 10.7 to 57.0% over baseline) and reduce transfusion requirements. Two double-blind placebo-controlled studies in patients undergoing haemodialysis or peritoneal dialysis have confirmed the superior efficacy of epoetin alfa administered intravenously or subcutaneously.

Improvements in functional ability and quality of life based on measures of energy levels, social life, relationships and leisure pursuits have been reported after epoetin alfa therapy was administered to correct anaemia in patients with end-stage renal failure.

Controlled randomised trials have shown epoetin alfa, administered intravenously or subcutaneously, to be superior to placebo in the correction of anaemia (haematocrit correction in 46 to 87% of patients vs 3% of placebo recipients in 1 study) and enhancement of quality of life in patients with predialysis renal failure. Epoetin alfa therapy does not appear to cause deterioration in renal function or progression to end-stage renal disease in these patients.

Response rates of at least 50% have been reported in uncontrolled studies of patients receiving epoetin alfa for anaemia associated with cancer or cytotoxic chemotherapy. These results have been confirmed by response rates of 32 to 82% with epoetin alfa compared with 2 to 15% with placebo in controlled trials. Reported increases in haematocrit and haemoglobin levels after active treatment ranged from 9.6 to 24.1% and 10.6 to 47.7% over baseline, respectively. Quality of life in terms of energy levels and ability to perform daily tasks also improved in responders. Subcutaneous epoetin alfa 150 to 300 IU/kg 3 times weekly for up to 4 months increased haemoglobin levels by a mean of 1.7 g/dl in a postmarketing study of 2030 patients with cancer and anaemia; transfusion requirements were decreased by 53%.

Small scale trials (n ≤ 20) have shown epoetin alfa treatment to raise haematocrit and haemoglobin levels in patients with anaemia associated with rheumatoid arthritis (RA).

Based on a reduction of at least 30 to 50% in transfusion requirements and/or an increase in haemoglobin levels of 1 to 2 g/dl, uncontrolled studies showed response rates of 0 to 56% in patients with myelodysplastic syndromes (MDS) after epoetin alfa therapy. Other studies with more stringent response criteria, including one randomised double-blind placebo-controlled trial, reported response rates of 12.5 to 26%. Efforts to identify consistently reliable predictors for response to epoetin alfa in these patients have not been successful to date.

Treatment with epoetin alfa during the 4-week period prior to surgery improved autologous blood donation capacity and decreased the severity of anaemia in patients undergoing cardiac or orthopaedic surgery. The number of patients requiring allogeneic blood transfusions was significantly reduced relative to placebo in 3 of 6 trials.

Tolerability

Tolerability data for epoetin alfa have mainly been obtained from patients with end-stage renal failure, in whom the incidence of hypertension secondary to the erythropoietic effect of the drug is 30 to 35%. In most of these patients, however, increased blood pressure can be managed successfully with monitoring of fluid status and antihypertensive medication. Thromboembolic events and seizures have also been reported in patients treated with epoetin alfa, but an association of the drug with vascular access thrombosis in patients undergoing haemodialysis has not been conclusively demonstrated (although increased anticoagulation with heparin may be required to prevent clotting of the dialyser). There is no evidence that epoetin alfa has any direct cerebrovascular effects.

Dosage and Administration

Intravenous or subcutaneous epoetin alfa 50 to 100 IU/kg 3 times per week is recommended initially in patients with CRF, titrated according to individual response until the target haematocrit of 30 to 36% is reached. In anaemia associated with cancer or chemotherapy, 150 IU/kg 3 times per week subcutaneously may be given initially and increased to 300 IU/kg 3 times per week if necessary after 8 weeks. The same initial dosage administered intravenously or subcutaneously has been suggested for the management of anaemia in MDS, with dosage escalation to a maximum of 300 IU/kg 3 times per week after 4 weeks if required.

Weekly subcutaneous or intravenous doses of 200 to 400 IU/kg for 3 to 4 weeks preoperatively may be used in patients donating autologous blood prior to surgery, and dosages of up to 600 IU/kg per week have been used in patients with RA.

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    Christopher J. Dunn & Antona J. Wagstaff

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Various sections of the manuscript reviewed by: P. Bárány, Department of Renal Medicine, Huddinge University Hospital, Huddinge, Sweden; P. Beris, Hôpital Cantonal Universitaire de Genève, Division d’Hématologie, Genève, Switzerland; S. Cascinu, Oncologia Medica, Università degli Studi di Ancona, Ancona, Italy; A.J. Erslev, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; K.N. Lai, Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; I.C. Macdougall, Directorate of Renal Medicine and Transplantation, St. Bartholomew’s Hospital, London, England; T. Pettersson, Department of Medicine, University of Helsinki, Helsinki, Finland.

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Dunn, C.J., Wagstaff, A.J. Epoetin Alfa. Drugs & Aging 7, 131–156 (1995). https://doi.org/10.2165/00002512-199507020-00007

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