This publication is provided for historical reference only and the information may be out of date.
Scope and Objectives
Most patients with chronic renal failure (CRF) will develop anemia at some point during the course of this progressive disease. Recombinant human erythropoietin (epoetin) makes it possible to increase hematocrit (Hct) levels; yet the benefits and harms associated with normalizing Hct in CRF patients need to be better understood. Recent controversy has focused on whether maintenance Hct levels should be above 36 percent in adult and adolescent CRF patients1 and above 30 percent in preadolescent CRF patients.2
This systematic review of the use of epoetin in patients with CRF sought primarily to compare outcomes of maintaining Hct >36 percent with outcomes of maintaining Hct in the 33 to <36 percent range. The published clinical trial evidence that addresses the specific comparison of primary interest for this systematic review was quite limited. To maximize the comprehensiveness of this report, the Evidence-based Practice Center (EPC) team decided, in consultation with advisory experts, also to synthesize and analyze results of studies reported only in abstract form; studies using any form of controlled design; and studies reporting intermediate outcomes known, or thought, to predict health outcomes. Therefore, this report includes associational studies as well as interventional studies -- studies in which the Hct in the control group was maintained in the 30 to <33 percent range as well as those in which the Hct in the control group was maintained in the 33 to <36 percent range.
Chapter 3, Results and Conclusions, is divided into three parts, with each part focusing on the relationship between Hct and health outcomes within a different population of interest. Part I addresses adult patients with CRF, Part II addresses pediatric patients with CRF, and Part III addresses subpopulations of interest (with or without CRF) who have clinical characteristics that are postulated to warrant maintaining Hct above 36 percent. The following key questions reflect the analytic framework for the systematic review.
Part I: Adult Patients with Chronic Renal Failure
- Based on evidence from interventional studies, what are the outcomes of maintaining target Hct above 36 percent compared with maintaining target Hct in the 30 to <36 percent range or, more specifically, in the 33 to <36 percent range?
- Based on evidence from associational studies, what are the outcomes of maintaining target Hct above 36 percent compared with maintaining target Hct in the 30 to <36 percent range or, more specifically, in the 33 to <36 percent range?
Part II: Pediatric Patients with Chronic Renal Failure
What is the effect on outcomes of maintaining an Hct in the following ranges:
- Above 30 compared with 27 to <30 percent, or
- Above 33 compared with 27 to <33 percent?
Part III: Subpopulations of Interest (with or without Chronic Renal Failure)
What is the effect on outcomes of maintaining the Hct level >36 percent as compared with 30 to <36 percent in the following patient subgroups (regardless of the presence of renal failure): (1) patients who have coronary artery disease, (2) patients who have congestive heart failure, (3) patients who live at high altitude, (4) patients who have arterial occlusive disease, (5) patients who have cerebrovascular disorders, (6) patients who have obstructive lung disease, and (7) patients who are in the adolescent age group?
Erythropoietin is an endogenous hormone, produced primarily in the kidney, which participates in regulating production of red blood cells (erythropoiesis). Two forms of recombinant human erythropoietin, which were given the generic names "epoetin alfa" and "epoetin beta" by the United States Adopted Names Council, were developed in the 1980s as treatments for anemia. The two epoetins replicate the protein sequence and biologic activity of the endogenous hormone and increase the number of red blood cells and thus the blood concentration of hemoglobin when given to individuals with functioning erythropoiesis. Indeed, when epoetin is used inappropriately in individuals with normal erythropoiesis (e.g., as a form of "blood doping" by competitive athletes), the red blood cell count can rise to a level that is life threatening (Adamson and Vapnek, 1991; Catlin and Hatton, 1991; Smith and Perry, 1992). The initial clinical use of epoetin was to treat anemia associated with CRF, especially patients on dialysis (i.e., endstage renal disease, ESRD).
Recombinant human erythropoietin replacement therapy (epoetin) is the mainstay of treatment for anemia secondary to ESRD, and the introduction of recombinant epoetin therapy in the late 1980s has dramatically changed the treatment of patients with anemia of chronic renal disease. Such patients no longer have to suffer the diminished quality of life associated with chronic severe anemia or be dependent on red blood cell transfusions. Presently, the prevailing practice is to maintain Hct below 36 percent, thus avoiding severe anemia, but maintaining a level below normal. One controversial issue is whether normalization of Hct will further improve health outcomes in CRF patients. This report is a systematic review of the evidence to compare the outcomes of maintaining Hct above 36 percent compared with the outcomes of maintaining Hct between 30 and 36 percent in patients with CRF. However, the comparison of primary interest in this report is the comparison between maintaining Hct above 36 percent and maintaining Hct between 33 and 36 percent.
Incidence, Prevalence, Costs, and Burden of Illness
The passage of the 1972 Social Security Amendment (P.L. 92-603) provided for Federal funding of health care coverage for dialysis and renal transplantation. Medicare's ESRD program has continued to be the only nationally funded, disease-specific program in the United States (Frankenfield, Prowant, Flanigan, et al., 1998). During the past 10 years, however, the incidence of ESRD has almost doubled. From 1987 to 1996, the rate grew from 142 per 1 million population to 276 per 1 million population, which translated in real numbers to 34,797 new cases of ESRD in 1987 increasing to 74,116 new cases in 1996 (National Institute of Diabetes and Digestive and Kidney Diseases, 2000). One major component in this increase appears to be an increased incidence of diabetes mellitus, particularly type 2. The ESRD incidence due to diabetes was 113 per 1 million population in 1996, which was a 150 percent increase over the 45 per 1 million population observed in 1987 (National Institute of Diabetes and Digestive and Kidney Diseases, 2000).
According to the U.S. Renal Data System, 335,014 U.S. patients in 1996 either received dialysis or a kidney transplant as life-saving treatment (National Institute of Diabetes and Digestive and Kidney Diseases, 2000). Particular minority populations are disproportionately afflicted with CRF. Compared with Caucasians, African-Americans and Native Americans have 4.5 and 3.7 times higher prevalence, respectively (National Institute of Diabetes and Digestive and Kidney Diseases, 2000). Although the number of cadaveric transplantations has only increased by 20 percent since 1987 (8,500 cases in 1996), the number of patients with ESRD receiving dialysis has doubled, and the number of patients on the transplantation waiting list has nearly tripled (Wolfe, Held, Hulbert-Shearon, et al., 1998). Studies have found lower rates of kidney transplantation and longer waiting times for minorities and women compared with whites and men (National Institute of Diabetes and Digestive and Kidney Diseases, 2000).
As the numbers of patients with ESRD have grown, so have the costs of the program. Medicare spent an estimated $10.96 billion in 1996, which was a 12.4 percent increase from the $9.74 billion spent in 1995. Although the ESRD population represented only 0.6 percent of the total Medicare population in 1994, their expenditures were 5.1 percent of the Medicare budget (National Institute of Diabetes and Digestive and Kidney Diseases, 2000).
Medicare's reimbursement for erythropoietin, which was approved in June 1989, has been in effect for a decade (Collins, Ma, Xia, et al., 1998). During this time, a number of studies have reported that increasing the Hct level from under 30 percent to more than 30 percent has decreased the occurrence of left ventricular hypertrophy (LVH) and has resulted in improved cognitive function, exercise tolerance, and quality of life (Collins, Ma, Xia, et al., 1998). Initially, Medicare's approved reimbursement for erythropoietin was capitated at $40 per administration. Within 3 years of Medicare coverage of erythropoietin treatment, the percentage of those with Hct values under 30 percent had decreased from nearly 60 percent of the patient claims to 40 percent.
Medicare then changed reimbursements to $11 per 1,000 units (U), which was comparable to 2,500 to 2,800 U/administration at the $40 cap. Costs began rising when the dosage pattern started to increase from 2,700 to almost 4,000 U/administration. Medicare responded by reducing reimbursement to $10 per 1,000 U. The agency also started denying payment to patients who had Hct levels over 36.5 percent. By the end of 1997, dosage patterns began to stabilize. Subsequently, Medicare has taken a more flexible stance and has allowed patients to sustain Hct levels up to 37.5 percent, while continuing to track patterns of usage and effects on morbidity and mortality (Collins, Ma, Xia, et al., 1998). However, medical justification (e.g., angina) is required in order to routinely maintain Hct above 36 percent.
Disease Biology, Natural History, Pertinent Clinical Features, Patient Populations, and Settings
Chronic renal failure may result from a variety of medical conditions that produce progressive, irreversible damage to the kidneys. The most common causes for CRF are diabetes mellitus and hypertension; other major causes include glomerulonephritis, polycystic kidney disease, and other urologic conditions (Brenner and Lazarus, 1994). Progressive renal injury follows a variable time course with gradual reduction in renal function often occurring over a period of years (Brenner and Lazarus, 1994). Ultimately CRF may result in ESRD requiring renal replacement therapy (i.e., hemodialysis or peritoneal dialysis) for patient survival.
Patients with CRF (either those receiving dialysis or those who are not yet on dialysis), commonly present with a normocytic, normochromic anemia (Bunn, 1994b; Faulds and Sorkin, 1989). A combination of factors appears to be responsible for this anemia. First, patients have an inappropriately low endogenous erythropoietin production, probably as a result of poorly functioning renal tissue (Bunn, 1994a, 1994b). Also, erythropoiesis appears to be inhibited by the presence of uremic solutes; these solutes also appear to shorten erythrocyte circulation half-life by increasing the osmotic fragility of the cells. The degree of anemia is roughly proportional to the degree of azotemia (Bunn, 1994b). Patients with endstage renal failure may demonstrate hemolysis, possibly because of metabolic or mechanical stresses from renal dialysis (Bunn, 1994b). Also, ferrokinetic studies have shown impaired incorporation of iron into circulating erythrocytes (Bunn, 1994b). Up to 25 percent of patients receiving chronic dialysis can develop a severe, transfusion-dependent anemia (Faulds and Sorkin, 1989).
Endstage renal disease is the final common pathway for a variety of pathologic conditions. Thus the ESRD population comprises a heterogeneous group of patients with a spectrum of clinical comorbidities. The type and severity of associated comorbidity may influence the type and severity of vascular pathology present in patients with ESRD. For example, a patient with ESRD resulting from severe diabetes mellitus would likely have more extensive systemic vascular abnormalities than a patient with ESRD resulting from chronic urinary obstruction or another process that selectively injures the kidneys and causes no systemic injury. Heterogeneity in the clinical spectrum of CRF and ESRD patients is a relevant consideration in analyzing the outcomes associated with increasing the Hct using epoetin.
Clinical Practice Guidelines for Anemia in Chronic Renal Failure
The National Kidney Foundation (NKF) established the Dialysis Outcomes Quality Initiative (DOQI™) in March of 1995. This initiative was developed following a series of conferences occurring in 1993 and 1994 that highlighted controversies in the quality of dialysis care. One major activity of the NKF-DOQI has been the development of evidence-based practice guidelines. The completed NKF-DOQI guidelines were published in the September and October 1997 supplement issues of the American Journal of Kidney Diseases and can also be accessed through the NKF Web site, www.kidney.org. Four topics were identified for initial guideline development: (1) hemodialysis adequacy, (2) peritoneal dialysis adequacy, (3) vascular access, and (4) anemia management. The NKF-DOQI guidelines were developed by four independent Work Groups composed of renal experts from diverse clinical disciplines. The Anemia Work Group comprised physician members representing the nephrology, hematology, and pediatric nephrology specialties and included other medical professionals such as nurses and pharmacists. The anemia guideline includes 28 separate recommendations addressing seven different management dimensions: anemia workup, target Hct/hemoglobin, iron support, administration of epoetin, inadequate epoetin response, role of red blood cell transfusion, and possible adverse effects related to epoetin therapy.
The NKF-DOQI guideline report on anemia provides a thorough review of the scientific evidence and expert opinion describing how epoetin should be administered to CRF patients as well as when adjuvant therapies may be necessary to optimize treatment response. Based on a review of the evidence, the NKF-DOQI work group concluded that target Hct should be 33 to 36 percent.
The NKF-DOQI guidelines recommend that iron status should be monitored and supplemental iron is necessary in order to maintain iron stores in a range that supports optimal erythropoiesis. Although oral iron may be administered initially, the work group noted that many CRF patients may be unable to maintain sufficient iron stores using oral iron alone. In most hemodialysis patients, ongoing blood loss necessitates the use of intravenously administered iron supplementation. Intravenous iron has much greater bioavailability than orally administered iron, and the evidence reviewed by the NKF-DOQI report showed that changing from oral to intravenous iron can result in increased Hct while using smaller amounts of epoetin.
The route of administration for epoetin appears to influence the efficiency in terms of the total dose of epoetin necessary to achieve and maintain a desired Hct level. Many studies have examined the effect of using subcutaneous versus intravenous epoetin, and the NKF-DOQI work group concluded that the evidence supported a recommendation to use subcutaneous epoetin as the preferred route of administration because of its increased efficiency. Because epoetin is more slowly absorbed when administered subcutaneously, elevated serum levels of epoetin are sustained over a longer period of time. The resulting effect is that target Hct level may be maintained using approximately 15 to 50 percent lower doses of epoetin when subcutaneous epoetin is substituted for intravenous epoetin.
Canadian Evidence-Based Recommendations
In 1995, a set of evidence-based recommendations for the clinical use of epoetin were published (Muirhead, Bargman, Burgess, et al., 1995). Over 200 scientific papers were reviewed by a group of Canadian medical professionals in the process of developing these recommendations that address five major questions: (1) Who should receive epoetin? (2) What should the target Hct be? (3) What is the best route of epoetin administration? (4) How should iron status be evaluated and managed? and (5) How should patients be monitored and followed up? The Canadian recommendations are similar with regard to route of epoetin administration and management of iron status and supplementation. However, the recommended target Hct for hemodialysis patients was 31.5 to 34.5 percent in the Canadian review, which is slightly lower than the target Hct recommended in the NKF-DOQI report.
European Best Practice Guidelines
The European renal community has established a Working Party including representatives from the European Renal Association/European Dialysis and Transplantation Association (ERA-EDTA) as well as from a cross-section of the national nephrology societies from European countries. The European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure were published in 1999 (Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure, 1999). The published guidelines include 28 separate sections covering a broad range of issues relating to anemia in CRF patients. The specific guideline addressing target hemoglobin concentration recommends that Hct should be maintained above 33 percent; however, the guideline does not specify an upper limit for target Hct and suggests that such targets should be individualized (Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure, 1999).
Recombinant human erythropoietin or "epoetin," was developed in the 1980s, after the human gene responsible for its production was cloned and expressed in vitro (Jacobs, Shoemaker, Rudersdorf, et al., 1985; Lin, Suggs, Lin, et al., 1985). The 165-amino acid mature recombinant protein is identical to the endogenous hormone with respect to its peptide sequence, and it has identical biologic activity (Amgen, Inc., 1999; Faulds and Sorkin, 1989; Ortho-Biotech, Inc., 1999).
The recombinant epoetin has been produced in two forms: alfa and beta (Halstenson, Macres, Katz, et al., 1991). Each differs from the other and from the endogenous form principally in the nature and composition of the carbohydrate chains attached to the peptide (McEvoy, 1999). The two recombinant forms may differ in their pharmacokinetic properties (Halstenson, Macres, Katz, et al., 1991). However, only the alfa form has been approved for marketing in the United States by the U.S. Food and Drug Administration (FDA) (McEvoy, 1999).
Epoetin cannot be administered orally; it is administered either by subcutaneous (sc) or intravenous (iv) injection (Amgen, Inc., 1999; Ortho-Biotech, Inc., 1999). Trials in patients with ESRD provide evidence that the drug is cleared more rapidly after iv than after sc administration (Albitar, Meulders, Hammoud, et al., 1995; Besarab, Flaherty, Erslev, et al., 1992; Canaud, Bennhold, Delons, et al., 1995; Kaufmann, Reda, Fye, et al., 1998; Paganini, Eschbach, Lazarus, et al., 1995; Virot, Janin, Guillaumie, et al., 1996). Slower clearance suggests a longer duration of exposure to biologically effective concentrations at a given dose when epoetin is administered subcutaneously rather than intravenously.
In most studies of patients who have CRF, the drug has been administered as an iv bolus 3 times weekly, generally in conjunction with hemodialysis treatments. The drug also has been administered parenterally via other routes convenient to the clinical situation (e.g., into the peritoneal cavity for patients on peritoneal dialysis). Also, the drug may be self-administered by the patient (Amgen, Inc., 1999; Ortho-Biotech, Inc., 1999).
Epoetin alfa is FDA-approved in the United States and marketed under the trade names Epogen® (Amgen, Inc., Thousand Oaks, CA) and Procrit® (Ortho-Biotech, Inc., Raritan, NJ). Both trade products are derived from the same source and are identical in composition (McEvoy, 1999).
Epoetin alfa has been FDA-approved for four uses (Table 1):
- The treatment of anemia associated with CRF (including patients on dialysis [for ESRD] and patients not on dialysis);
- The treatment of anemia related to therapy with zidovudine in HIV-infected patients;
- The treatment of anemia in patients with nonmyeloid malignancies where anemia is an effect of concomitantly administered chemotherapy; and
- The treatment of anemic patients (hemoglobin >10 to <13 g/dL) scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions and patients at high risk for perioperative transfusions with significant, anticipated blood loss (Amgen, Inc., 1999; Ortho-Biotech, Inc., 1999).
Amgen, Inc. is licensed to market Epogen® for the treatment of dialysis patients with anemia of ESRD; Ortho-Biotech, Inc., is licensed to market Procrit® for the treatment of all other FDA-approved uses, including the treatment of anemia in predialysis patients.
The drug has been used off-label for a variety of other uses, including anemia of prematurity (Faulds and Sorkin, 1989), anemia of chronic disease (e.g., rheumatoid arthritis) (Faulds and Sorkin, 1989; Pincus, Olsen, Russell, et al., 1990; Salvarani, Lasagni, Casali, et al., 1991; Vreugdenhil and Swaak, 1990), anemia of myelodysplastic syndromes (Adamson, Schuster, Allen, et al., 1992; Ludwig, Fritz, Leitgeib, et al., 1993; Stein, Abels, and Krantz, 1991), sickle-cell anemia (Faulds and Sorkin, 1989), anemia of multiple myeloma (Ludwig, Fritz, Leitgeb, et al., 1993), and anemia following high dose chemotherapy with stem-cell support (Henry, 1998).
In patients with CRF receiving epoetin therapy, the most common adverse effect of the drug is hypertension, occurring in approximately 24 percent of such patients (Amgen, Inc., 1999; Ortho-Biotech, Inc., 1999). Other less common but more serious adverse effects of the drug include hypertensive encephalopathy, seizures, and thrombotic/vascular events (Amgen, Inc., 1999; Ortho-Biotech, Inc., 1999).
Unpublished International Clinical Trials
During the course of conducting this systematic review, the EPC team followed the status of two additional international studies that evaluated the effects of increasing Hct above 36 percent in patients with CRF (Jacobs, 1999): (1) a multicenter randomized controlled trial (RCT) conducted in Canada by Foley, Parfrey, Morgan, et al. (1998) comparing normalization of Hct (40.5 percent target) with partial correction of anemia (30 percent target) in 146 hemodialysis patients with asymptomatic cardiomyopathy; and (2) a multicenter RCT conducted in Scandinavia comparing normalized Hct (target of 43.5 to 48 percent in males, 40.5 to 45 percent in females) with partial correction of anemia (target 27 to 36 percent) in 416 patients with CRF (293 hemodialysis, 51 continuous ambulatory peritoneal dialysis, and 72 predialysis) ("Scandinavian Multicentre Trial," see description in Jacobs, 1999). At the time this report was completed, results of the Canadian study had been published in two abstracts (Foley, Parfrey, Morgan, et al. 1998; Wells, Coyle, Lee, et al. 1998), and these findings are described in this systematic review. No results of the Scandinavian study were available.
The normal range of blood hemoglobin level is 16 ± 2.0 g/dL in males and 14 ± 2.0 g/dL in females (Perkins, 1999). Employing the commonly used conversion factor of multiplying by 3 to convert hemoglobin to Hct, normal Hct ranges are approximately 48 ± 6 percent for males and 42 ± 6 percent for females.
The normal range of blood hemoglobin level for children between the ages of 3 months and 10 years is 12.2 ± 2.3 g/dL (Perkins, 1999). Employing the commonly used conversion factor of multiplying by 3 to convert hemoglobin to Hct, normal Hct range is approximately 36.6 ± 6.9 percent.
Most citations for well-established points in this background chapter are to relatively recent reviews, rather than to the original publications. Interested readers are referred to the cited reviews to identify the original sources for these observations.
Agency for Healthcare Research and Quality (US), Rockville (MD)
Flamm CR, Aronson N, Bohn R, et al. Use of Epoetin for Anemia in Chronic Renal Failure. Rockville (MD): Agency for Healthcare Research and Quality (US); 2001 Aug. (Evidence Reports/Technology Assessments, No. 29.) 1, Introduction.