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Epoetin Alfa
Clinical Evolution of a Pleiotropic Cytokine
David H. Henry, MD;
Peter Bowers, MD;
Michael T. Romano, PhD;
Robert Provenzano, MD
Arch Intern Med. 2004;164:262-276.
ABSTRACT
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Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin–interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.
INTRODUCTION
Recombinant human erythropoietin (epoetin alfa) was one of the first therapies brought to the clinic via recombinant DNA technology,1-2 with its initial introduction as a hormone therapy in the treatment of anemia in patients with chronic kidney disease (CKD).3-6 A decade has passed since several randomized controlled clinical trials confirmed the benefits of epoetin alfa therapy for anemia in zidovudine-treated patients with human immunodeficiency virus (HIV) infection,7-8 which was the first clinical application of the drug in a setting of elevated, yet still inadequate, endogenous erythropoietin levels.9 During this period, indications for epoetin alfa in the United States and worldwide have expanded considerably (Table 1).
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Table 1. Timeline of Approved Indications for Epoetin Alfa (Varies by Country and Fomulation)
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Greater understanding of the pathophysiology of anemia in numerous diseases and conditions and the interactions of erythropoietin, iron, and erythropoiesis10 has accompanied the growing clinical investigation and therapeutic use of epoetin alfa. Anemia is also independently associated with increased mortality in various diseases and conditions. New insights into the relationships among hemoglobin (Hb) levels, symptoms of anemia, and quality of life (QOL) are prompting the reevaluation of tolerating lower Hb levels and the traditional use of Hb levels below 10 g/dL as the trigger for therapeutic intervention in many settings and patient populations. Observations across several diseases also raise the possibility that treatment and correction of anemia with epoetin alfa may be associated with improved survival.11-13 In addition to ongoing clinical evaluation in various patient populations and conditions, preclinical studies have now established erythropoietin to be a pleiotropic cytokine with antiapoptotic activity,14-16 as well as potential neuroprotective effects against central nervous system (CNS) injury. This review summarizes the developments and insights gained regarding the biology and clinical use of epoetin alfa since its initial introduction, focusing on clinical uses other than anemia in patients with advanced stages of CKD (ie, end-stage renal disease), as well as important areas of ongoing and new research that are anticipated to widen its therapeutic potential.
BIOLOGY OF ERYTHROPOIETIN
Erythropoietin is a glycoprotein produced primarily in the kidneys that stimulates the division and differentiation of committed erythroid progenitors in the bone marrow.17-19 Plasma erythropoietin levels remain relatively constant when Hb levels remain at or above 12 g/dL but begin to rise rapidly and markedly when the Hb level decreases below 12 g/dL (Figure 1).20 It takes 3 to 4 days following erythropoietin stimulation for circulating reticulocytes to increase.21 Depending on the degree of anemia, maturation of circulating reticulocytes into mature red blood cells (RBCs) may take an additional 1 to 3 days.20 Thus, any clinically significant increase in Hb levels is usually not observed in less than 2 weeks following erythropoietin stimulation and may require up to 6 weeks in some patients.
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Figure 1. The response of erythropoietin secretion to anemia. Hb indicates hemoglobin. Reprinted with permission from Hillman and Finch.20
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Epoetin alfa is the recombinant equivalent of the endogenous cytokine, with an identical amino acid structure and indistinguishable biologic activity both in vitro and in vivo.1-2,22 Over the last decade, greater efforts to more completely describe the biology of erythropoietin in humans have been undertaken, particularly to identify roles and actions of the cytokine in hematopoiesis and other biologic processes.
Erythropoietin has high affinity for the erythropoietin receptor expressed on the surface of erythroid cells. This receptor belongs to the cytokine receptor family that includes growth hormone, prolactin, various colony-stimulating factors, leptin, and several interleukins.15, 23 In addition to its essential role in erythropoiesis, the erythropoietin receptor also is expressed in mast cells and megakaryocytes, as well as in nonhematopoietic tissues (eg, gastric mucosa, vascular smooth muscle, and brain neurons).16, 24-27 In brain neurons, a role for erythropoietin receptor signaling during ischemia-associated neuronal angiogenesis has been suggested.28-29 In addition, erythropoietin acts to inhibit programmed cell death (apoptosis) of erythroid progenitor cells,30 as well as in neurons following cerebral ischemia and metabolic stress.14 Other proposed neuroprotective mechanisms for erythropoietin include antioxidation31 and a direct neurotrophic effect.32
DOSING OF EPOETIN ALFA
Epoetin alfa was initially administered intravenously 3 times weekly (TIW) to patients with CKD who were undergoing dialysis to mimic the normal physiologic environment and to allow the patient to receive the drug simultaneously with dialysis.3-5 Additional experience demonstrated that the drug also could be administered subcutaneously (SC) at the same or a somewhat reduced dose and schedule.33 The TIW dosing regimen was used in clinical trials evaluating epoetin alfa for subsequent indications, but investigation of alternative, more convenient dosing schedules followed.34-36 Pharmacokinetic and pharmacodynamic studies in healthy subjects established that epoetin alfa administered SC at intervals of 7 to 10 days resulted in significant increases in reticulocyte counts34, 36 and Hb levels.34 A subsequent randomized, parallel-design study in healthy adults demonstrated that epoetin alfa, 150 U/kg SC TIW, and 40 000 U SC once weekly for 4 weeks were clinically equivalent regimens, producing similar increases in percentage of reticulocytes, Hb, and total RBCs.37 Once-weekly epoetin alfa dosing has been shown to significantly increase Hb levels in anemic patients with CKD,38 patients scheduled for major orthopedic surgery,35 anemic patients with cancer receiving chemotherapy39 or sequential or concurrent radiation plus chemotherapy,40-41 anemic HIV-positive patients (including patients receiving highly active antiretroviral therapy [HAART] with or without zidovudine),42-43 and hepatitis C virus (HCV)-infected patients who develop anemia while receiving ribavirin–interferon alfa therapy.44 The efficacy and safety profiles of once-weekly epoetin alfa dosing in these populations were similar to those observed with TIW dosing. The once-weekly dosing regimen is now widely used in these patient populations (Table 2). Studies also are in progress in anemic patients with cancer receiving chemotherapy,45-46 patients with CKD not undergoing dialysis,47 and HIV-positive patients to evaluate alternative epoetin alfa dosing regimens, including higher starting doses (eg, 60 000 U SC once weekly)45-46 and extended maintenance dosing intervals (eg, every 2-4 weeks).46-47
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Table 2. Once-Weekly Epoetin Alfa Dosing and Administration Schema35,39,40,43
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Traditionally, patients with anemia were not treated until Hb levels dropped below 10 g/dL, at which time RBC transfusions often were administered empirically. Concerns about potential HIV and other infections in the 1980s influenced the treatment of mild to moderate anemia because no alternative was available. Transfusions were generally withheld until Hb levels declined to 7 to 8 g/dL or the patient manifested symptoms of severe anemia. Normal physiologic stimulation of endogenous erythropoietin begins when Hb level falls below 12 g/dL. Based on this standard and data from anemic patients with cancer who demonstrate a significant relationship between QOL and Hb levels from 8 to 14 g/dL—with the greatest improvements in QOL occurring as Hb levels increased from 11 to 12 g/dL48—it may be more appropriate to consider treating anemic patients at Hb levels lower than 12 g/dL rather than waiting until more severe anemia develops.48-49 This strategy would more closely mimic the body's normal response to inadequate tissue oxygenation and low Hb levels.20
IRON REQUIREMENTS WITH EPOETIN ALFA USE
Transferrin saturation and serum ferritin should be monitored both prior to and during epoetin alfa therapy. In addition, patients who fail to respond or to maintain a response to recommended epoetin alfa doses should be evaluated for the presence of an underlying infectious, inflammatory, or malignant process; occult blood loss; underlying hematologic disease (eg, thalassemia and refractory anemia); vitamin deficiencies (folate and vitamin B12); hemolysis; aluminum intoxication; and osteitis fibrosa cystica. In contrast to absolute iron deficiency, which results from inadequate iron stores, functional iron deficiency describes the failure to provide iron quickly enough to meet the demands of erythropoiesis.50 Inflammatory cytokines associated with the anemia of chronic disease are believed to inhibit the release of iron in storage, limiting the rate of RBC production. In particular, in clinical settings such as cancer and HIV and in patients with CKD undergoing dialysis, epoetin alfa stimulation of RBC production may surpass the rate of iron mobilization from iron stores to the labile iron pool, despite the existence of adequate iron in storage form.51 This results in a rapidly depleted labile iron pool, delaying a response to epoetin alfa and requiring iron supplementation to achieve or to maintain the effectiveness of epoetin alfa. Oral iron formulations cannot always provide iron quickly enough to support the accelerated erythropoiesis that occurs with epoetin alfa, and intravenous iron supplementation may be required.51-54
CLINICAL EVOLUTION
Chronic Kidney Disease
As defined by the National Kidney Foundation (NKF), CKD describes patients with chronically reduced renal function, including those with chronic allograft dysfunction and those with end-stage renal disease.55 Normochromic, normocytic anemia occurs in most patients with CKD and is associated with physiologic abnormalities including cardiac dysfunction, impaired cognitive function, impaired immune response, growth retardation in pediatric patients, reduced QOL, and decreased patient survival.53 In use since 1986,3 epoetin alfa has proven safe and effective for management of anemia in adult and pediatric patients with CKD, both prior to and during dialysis.4-5,56-60 Effective treatment of the anemia of CKD may improve survival (in predialysis patients and patients undergoing dialysis),11, 61 decrease the risk of hospitalization,62 decrease morbidity,62-63 slow disease progression,11, 64-65 and improve QOL.55 The NKF guidelines now recommend target Hb levels of 11 to 12 g/dL and hematocrit (HCT) values ranging from 33% to 36%,55 which are associated with marked improvement in oxygen utilization; muscle strength and function; cognitive and brain function66-69; cardiac function63, 70-71; sexual function; and QOL.55
Early CKD
A novel approach to managing anemia and its complications in CKD is to start epoetin alfa therapy in patients with early CKD at the first indication that Hb levels are falling below normal.72 Because cardiovascular disease is common in patients with CKD and anemia is an independent risk factor for left ventricular hypertrophy in predialysis patients with CKD,70 early treatment of anemic patients with CKD may prevent the cardiovascular dysfunction (eg, left ventricular hypertrophy, cardiac failure, and stroke) or its progression commonly observed in anemic patients with end-stage renal disease.72-74 As in diabetic patients with microalbuminuria who are treated for maximum blood pressure control and with angiotensin-converting enzyme inhibitors to prevent progression to macroalbuminuria or deteriorating renal function,75 treatment of anemia in patients with early CKD may have the potential to alter the disease course. An additional goal in early CKD is to maintain exercise capacity and QOL. Patients also would likely be in better overall health when dialysis becomes necessary.
For an early treatment strategy to be optimally used, a clearer understanding of the scope of anemia in early CKD is needed. In a recent preliminary analysis, 48% of 1716 patients with early CKD (serum creatinine concentration: women,  1.5 mg/dL [132.6 µmol/L], or men, 2.0 mg/dL [176.8 µmol/L], but  6 mg/dL [530.4 µmol/L] within the past 12 months) had an Hb level of 12 g/dL or lower, including 9% with an Hb level of 10 g/dL or lower.76 As might be anticipated, a relationship between anemia severity and worsening renal function also was observed; approximately 52% of patients with a creatinine clearance of 30 mL/min or less also had an Hb level of 12 g/dL or lower.76 These initial findings suggest a high prevalence of anemia in patients with earlier stages of CKD. In this context, Provenzano et al38 recently conducted a large, prospective, multicenter study in patients with early CKD (serum creatinine concentration: women, 1.5 mg/dL [132.6 µmol/L]; men, 2.0 mg/dL [176.8 µmol/L], but 6 mg/dL [530.4 µmol/L] over 16 weeks) and showed that once-weekly epoetin alfa treatment improved Hb and HCT values from a baseline of 9.2 g/dL and 27.5%, respectively, to 11.9 g/dL and 36.2%, respectively, over 16 weeks. Transfusion rates were reduced from 11.1% to 0.5% in these patients, and QOL measures also showed improvement throughout the 16-week treatment period.
Treatment with epoetin alfa prior to initiation of dialysis also may improve survival in patients with CKD. A retrospective analysis performed on data from 4866 patients with end-stage renal disease, of whom 1107 (23%) were treated with epoetin alfa prior to initiation of dialysis,11 showed that patients treated with epoetin alfa before starting dialysis had a lower mortality risk compared with patients who did not receive epoetin alfa treatment before dialysis (adjusted relative risk, 0.80). The greatest survival benefit was observed in patients with HCT values greater than 31.8% prior to dialysis (adjusted relative risk, 0.67; P<.001). Patients also received the most benefit during the first 19 months of dialysis (adjusted relative risk, 0.81), with no sustained survival advantage among patients undergoing dialysis for more than 31 months relative to patients who did not receive epoetin alfa prior to dialysis.
Early detection and intervention are key to the overall management strategy of patients with CKD.77 This includes managing primary comorbidities (eg, diabetes and hypertension), preventing uremic complications (eg, anemia, acidosis, and malnutrition), and instituting appropriate measures to delay disease progression (eg, treatment with angiotensin-converting enzyme inhibitors, lipid management, and protein restriction). Correction of anemia plays a principal role in effectively managing many of these issues.77
HIV/AIDS
Anemia is the most common hematologic abnormality of HIV infection, and its frequency and severity usually increase as infection progresses to immunologic and clinical AIDS.78-80 The first antiretroviral agent, zidovudine, was a well-recognized cause of bone marrow suppression and anemia, especially with the higher dosages used prior to the introduction of HAART.7-8 The evaluation of epoetin alfa as a potential therapy for anemia in patients with HIV or AIDS who were receiving zidovudine7 was prompted by the growing HIV/AIDS epidemic; the anticipated increase in transfusion requirements; concerns over the immunosuppressive effect of transfusions in this population; and the fact that, although elevated above normal, plasma erythropoietin levels in patients with HIV or AIDS were usually inadequate for the degree of anemia.9
Four placebo-controlled clinical trials including 255 evaluable patients demonstrated that epoetin alfa administered TIW significantly increased HCT (P<.001) and decreased transfusion requirements (P = .003) in patients with HIV or AIDS receiving zidovudine.8, 81 These results were confirmed in an analysis of data from 1943 anemic patients with AIDS who participated in an open-label, multicenter, epoetin alfa treatment investigational new drug protocol.82 The increase in HCT values and reduction in transfusion requirements were comparable with those observed in the controlled trials, and epoetin alfa therapy did not accelerate disease progression. A subgroup analysis of 523 patients who participated in the open-label study who were not receiving zidovudine found that the increase in HCT values and decrease in transfusion requirement also were comparable with those observed in patients receiving zidovudine.83 Subsequent clinical trials have demonstrated that once-weekly epoetin alfa therapy (40 000-60 000 U SC for up to 16 weeks) also results in significant improvements in Hb and self-reported QOL parameters from baseline to final evaluation, regardless of whether antiretroviral therapy includes zidovudine, with QOL improvements corresponding to increases in Hb.42-43
The introduction of HAART in 1996 had a dramatic impact on the treatment of HIV infection, significantly slowing disease progression as well as accompanying signs and symptoms and improving long-term prognosis for many patients. With the lower zidovudine dosages in current regimens, anemia was perceived as a less important clinical issue.84 However, recent data suggest that mild to moderate anemia remains prevalent among HIV-positive patients receiving HAART therapy.85-88 In a subset analysis of data from the EuroSIDA study, a large prospective, observational study of more than 7300 nonselected HIV-positive patients in Europe, anemia resolved after 12 months in approximately 30% of patients who had anemia at initiation of HAART, but mild to moderate anemia remained evident in 46% of patients.87
Many studies suggest that anemia is independently associated with disease progression and an increased risk of mortality in patients with HIV infection.12, 79, 86, 89 The consistency of this observation regardless of heterogeneous patient populations, varied treatments, and different definitions of anemia underscores the strength of its reported association.84 This association appears to be maintained in the HAART era,87, 90-92 and data from recent studies further suggest that recovery from anemia may have a beneficial impact on survival of HIV-positive patients.12, 79, 93 In an analysis of data from the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project, patients who recovered from anemia (Hb level >10 g/dL after diagnosis of anemia and Hb level of at least 1 g/dL higher than the level at the time of anemia diagnosis) had a significantly (P<.001, log-rank test) longer median survival time than patients who did not recover from anemia, regardless of initial CD4 cell count.79 In a study of 2348 HIV-positive patients treated at a large urban HIV clinic from 1989 to 1996, use of epoetin alfa for the treatment of anemia (n = 91) was associated with a decreased risk of dying (relative hazard, 0.57; P = .002).12 The observation was similar when only those patients who developed anemia (n = 498) were evaluated, adjusting for other prognostic factors. In 1203 patients from the cohort of HIV patients at this clinic who were monitored for a median of 2 years from 1996 to 1999 and included patients receiving HAART, patients with a Hb level of 9 to 11 g/dL had a 1.7-fold increase in the relative hazard for death; in addition, recovery from anemia (2-g/dL increase in the Hb level) was associated with a relative reduction in risk of death of 40% compared with nonrecovery from anemia—a notable finding.93
Collectively, these data highlight the ongoing importance of anemia monitoring in HIV-positive patients as the disease progresses, as well as the value of maintaining near-normal Hb levels to potentially improve QOL and functional ability and survival, despite recent advances in antiretroviral therapy.84 Some experts suggest that treatment of anemia in HIV-positive patients should be considered at an Hb level lower than 12 g/dL in men and lower than 11 g/dL in women, increasing the Hb level to 12 g/dL or higher in men or 11 g/dL or higher in women.84 Epoetin alfa may be appropriate initial therapy for treatment of HIV-related anemia when the Hb level is decreasing or has decreased slowly and also may be appropriate for patients who require repeated transfusions with associated frequent hospitalizations.84
Cancer
Anemia is a frequent, often debilitating complication of cancer and its treatment. Fatigue, the most common symptom associated with anemia, affects most patients with cancer during the course of their disease and treatment, with many of these patients experiencing fatigue daily or reporting that fatigue significantly affects their daily routines.94-95 Historically, reporting of anemia as a toxic effect in chemotherapy studies was mainly focused on the more severe grades.96 Mild to moderate anemia, however, occurs in 50% to 75% of adults receiving the most common single agents and combination regimens used to treat major nonmyeloid malignancies.96 A recent systematic, quantitative review of available literature suggests that anemia may be an independent prognostic factor for survival in patients with cancer.97 The overall estimated increased relative risk of death, after adjusting for other factors, was 65%; anemia was associated with significantly shorter survival times in patients with lung cancer, head and neck cancer, prostate cancer, or lymphoma. The anemia of cancer most closely resembles the anemia associated with chronic disease, with patients demonstrating serum erythropoietin levels that are elevated above normal but not as high as levels observed in patients with similar decreases in Hb level caused by iron deficiency or hemolytic anemia.98 It appears that patients with cancer experience a blunted erythropoietin response to anemia,98 as well as inadequate erythropoietin production,99 making higher doses of epoetin alfa necessary to correct anemia in this setting.
Epoetin alfa (150-300 U/kg TIW) has been shown in randomized, double-blind, placebo-controlled clinical trials to effectively increase Hb levels and reduce transfusion requirements in anemic patients with cancer treated with cisplatin-containing or non–cisplatin-containing chemotherapy.100-101 Three additional large, prospective, community-based trials further established the efficacy of epoetin alfa (150-300 U/kg TIW [N>4370] or 40 000-60 000 U once weekly [N = 3012]) in increasing Hb levels and decreasing transfusion requirements in anemic patients with cancer receiving platinum or nonplatinum chemotherapy.39, 102-103 A recent randomized, double-blind, placebo-controlled trial confirmed the results of the community-based trials, showing that, compared with placebo, epoetin alfa significantly reduced transfusion requirements (P = .006), increased Hb levels (P<.001), and improved QOL (P<.01).13 Further, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P = .13), with Cox regression analysis demonstrating an estimated hazard ratio of 1.309 (P = .052), suggesting that the mortality risk during the median 26-month follow-up period was approximately 31% higher for patients receiving placebo than for those receiving epoetin alfa. This study was not powered to assess survival, however, and the protocol did not control for variables that may influence survival (eg, disease stage, bone marrow involvement, intensity of chemotherapy, and disease progression).
Epoetin alfa also is undergoing active investigation for the treatment of anemia in pediatric patients with Hodgkin disease, acute lymphocytic leukemia, and non-Hodgkin lymphoma who are receiving chemotherapy, as well as in patients with cancer who receive radiotherapy only. Randomized controlled trials show that epoetin alfa treatment can significantly reduce transfusion incidence, increase mean Hb level, and improve QOL in patients with multiple myeloma.104-106 Epoetin alfa also may allow disease downstaging in B-chronic lymphoproliferative disorders with long-term use.107 Epoetin alfa administration in mice bearing multiple myeloma tumors has been shown to markedly prolong survival and reduce mortality, suggesting that epoetin alfa may act as an antitumor therapeutic agent in addition to its role in erythropoiesis.108 Results of several clinical studies also suggest that use of epoetin alfa as an adjunct to radiotherapy can increase and maintain Hb levels and improve QOL during radiotherapy administered alone or either sequentially or concomitantly with chemotherapy.40-41,109-112 Preliminary results in patients with head and neck cancer further suggest that epoetin alfa therapy may improve locoregional control and survival rates to levels observed in patients with normal pretreatment Hb levels.113-114 Additional clinical trials designed specifically to assess the potential impact of epoetin alfa on survival of patients with cancer are ongoing.
To confirm early clinical studies suggesting that epoetin alfa can effectively correct anemia in patients with advanced cancer without regard to chemotherapy use,100, 115-118 Quirt et al119 recently demonstrated that epoetin alfa administration to patients with nonmyeloid malignancies, including a large cohort of anemic patients (n = 183) not receiving chemotherapy, significantly improved Hb levels and decreased transfusion use, with increases in Hb levels positively correlating with significant improvements in QOL and changes in Eastern Cooperative Oncology Group performance scores. These results indicate that patients with cancer-related anemia who are not receiving chemotherapy can achieve substantial clinical benefits with epoetin alfa treatment.
Surgery
Despite significant improvements in the safety of the blood supply in recent years, efforts continue to refine existing blood conservation programs and develop new ways to minimize perioperative allogeneic blood exposure. Epoetin alfa has been shown in placebo-controlled trials to significantly decrease allogeneic transfusion requirements and increase preoperative Hb levels in mildly anemic (Hb level >10 g/dL to 13 g/dL) patients undergoing major elective orthopedic procedures.120-122 In addition, epoetin alfa therapy resulted in comparable or significantly higher mean Hb levels preoperatively, postoperatively, and at discharge compared with preoperative autologous donation patients undergoing total joint arthroplasty surgery (P<.001).123 These results suggest that epoetin alfa may effectively allow bloodless orthopedic surgery in many patients.124 Epoetin alfa also has been shown to reduce perioperative exposure to allogeneic blood in patients undergoing radical retropubic prostatectomy.125-127 The results of these trials indicate that perioperative epoetin alfa administration is a safe, well-tolerated, effective, and cost-equivalent alternative to preoperative autologous donation.128
Quality of Life
From the patient's perspective, QOL has become an increasingly important consideration in health care management and therapeutic decisions for individual patients. Numerous studies have now demonstrated a correlation between a positive response to epoetin alfa therapy and improved QOL (overall QOL, energy level, and activity level) in anemic patients with CKD,6, 38, 66 cancer,13, 39, 48, 102-103,118 and HIV infection.8, 43, 129-130 Clinically relevant insights are emerging regarding the relationship between Hb levels and patient well-being and functional outcomes. In anemic patients with cancer treated with chemotherapy, significant improvements in self-reported QOL parameters and functional status have been reported by patients demonstrating a hematologic response to epoetin alfa,13, 39, 102-103 with improvements occurring independent of tumor response (Figure 2).102-103 An incremental analysis of the clinical and outcomes data from the combined results of the 2 community-based trials using TIW epoetin alfa dosing102-103 demonstrated a significant (P<.01), nonlinear relationship between Hb level and QOL over the Hb level range of 8 to 14 g/dL, with the greatest improvement in QOL occurring when the Hb level increased from 11 to 12 g/dL (range, 11-13 g/dL).48 These studies in anemic patients with cancer indicate that Hb levels lower than 12 g/dL are associated with suboptimal degrees of overall QOL and functional abilities and are consistent with a large body of evidence in anemic patients with renal dysfunction that functional status is optimized at a Hb level of 12 g/dL. Collectively, these results have had a significant impact on the understanding of anemia and its relationship to patient well-being, suggesting that optimal management of anemia contributes substantially to improving QOL and functional status and that more aggressive treatment of mild to moderate anemia in multiple patient populations may be warranted.
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Figure 2. Quality of life parameters (Functional Assessment of Cancer Therapy–Anemia [FACT-An]) analyzed based on changes in hemoglobin levels and tumor response from baseline to final assessment. Asterisk indicates significantly (P<.01) different from baseline; dagger, significantly (P<.01) different from adjacent hemoglobin change group; and double dagger, significantly (P<.05) different from adjacent hemoglobin change group. Adapted with permission from Demetri et al.103
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NEW AREAS OF RESEARCH
Congestive Heart Failure
Patients with congestive heart failure often develop anemia, which generally worsens with increasing heart failure severity.131-135 The anemia appears to occur despite plasma erythropoietin levels that increase progressively with increasing New York Heart Association (NYHA) severity.135 Based on animal and human studies, the ischemic or hypertrophied heart seems to be more sensitive than healthy myocardium to anemia, including very small changes in Hb level, which result in a marked worsening of ischemia and impairment in cardiac function in the diseased heart.136-137 Conversely, chronic severe anemia results in salt and fluid retention that appears to improve when the anemia is corrected.138 In anemic patients with CKD, treatment with epoetin alfa has resulted in reductions in left ventricular hypertrophy, prevention of left ventricular dilatation, and improvement in left ventricular ejection fraction, stroke volume, and cardiac output.139-143 Thus, correction of anemia in patients with congestive heart failure may improve myocardial function.
In a recent retrospective analysis, the prevalence and significance of mild anemia (Hb level <12 g/dL) in 142 patients with heart failure were shown to increase with heart failure severity, ranging from 9% in patients with NYHA class I heart failure to 79% of patients with NYHA class IV disease.144 Of note, 19% of patients with mild heart failure (NYHA class II) and 53% of patients with moderate disease (NYHA class III) were anemic and had concomitant serum creatinine levels ranging from 1.9 to 2.4 mg/dL (168-212 µmol/L), indicating some degree of renal insufficiency even in patients with relatively mild cardiac impairment. A subset of 26 patients with NYHA class IV heart failure, despite maximally tolerated therapy for at least 6 months and Hb levels lower than 12 g/dL, were enrolled in an intervention trial and received epoetin alfa (mean ± SD dosage, 5227 ± 455 U SC once weekly) and intravenous iron supplementation for a mean ± SD of 7.2 ± 5.5 (range, 4-15) months. In this subset, epoetin alfa therapy was associated with significant improvements in Hb levels and functional status and a 28% increase in left ventricular ejection fraction compared with baseline (Table 3). These improvements correlated with a significant reduction in oral and intravenous furosemide administration from baseline, a 92% decrease in hospitalizations compared with a similar period prior to initiation of epoetin alfa therapy, and a decrease in the rate of renal failure progression. No adverse events associated with epoetin alfa therapy were reported. Thus, treatment of anemia in patients with even mild to moderate heart failure may ameliorate progression of CKD and congestive cardiomyopathy. If successful treatment of anemia can improve cardiac function and reduce hospitalizations in patients with congestive heart failure who have or develop anemia, epoetin alfa therapy may have an important role in the overall management of major cardiovascular disease. Further evaluation is warranted, and a randomized, controlled trial is ongoing.
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Table 3. Hematologic and Clinical Findings in 26 Patients With Heart Failure at Baseline and Following Epoetin Alfa Therapy*144
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CNS Disorders
There is considerable interest in agents that might have neuroprotective effects associated with various CNS insults such as head trauma, anoxic injury, and stroke. Epoetin alfa administered via intracerebroventricular injection appears to have such neuroprotective properties in animal models of hypoxic and/or ischemic stress.28, 145 In studies using various in vitro and animal models of human CNS disorders, epoetin alfa had a protective effect against several forms of neuronal damage occurring in stroke, head trauma, epilepsy, and autoimmune encephalitis.28-29,145-147 Astrocytes and neurons also can produce erythropoietin under hypoxic or ischemic conditions.27, 148-153 However, physiologic erythropoietin production alone cannot meet the oxygen demand needed to adequately respond to acute and severe hypoxic and/or ischemic neuronal stress, such as that which occurs following cerebrovascular accident, blunt head trauma, or status epilepticus.146 Thus, it is possible that exogenous epoetin alfa administration following neuronal stress may augment the activity of endogenous erythropoietin in the CNS.
Intracerebrovascular injection is clearly not practical in the clinical setting and, until recently, systemically administered epoetin alfa had not been seriously evaluated in animal models because conventional wisdom suggested that large glycosylated molecules (eg, epoetin alfa) were not capable of crossing the blood-brain barrier. However, certain large proteins are transported into the CNS via binding to receptors on the capillary endothelium.154-155 Using immunocytochemistry techniques, th |
