Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of the Full Report
An estimated 74,116 patients developed endstage renal disease (ESRD) in 1996; most have anemia as a result of their chronic renal failure (CRF). Epoetin offers patients with anemia of CRF the potential to target hematocrit (Hct) to a level considered normal for a healthy adult or child; yet the benefits and risks of using epoetin to normalize Hct in these patients as compared with partially correcting the anemia have not been well established.
The normal range of blood hemoglobin level for adults is 16 ± 2.0 g/dL in males and 14 ± 2.0 g/dL in females. 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. 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.
This systematic review seeks primarily to compare outcomes of maintaining a target Hct above 36 percent with maintaining a target Hct in the 33 to < 36 percent range in patients with CRF. The published clinical trial evidence that addresses the comparisons of primary interest for this systematic review is quite limited.
To maximize the comprehensiveness of this report, the Evidence-based Practice Center (EPC) that conducted this review decided, in consultation with advisory experts, to synthesize and analyze results of:
Therefore, this report includes associational studies as well as interventional studies—studies in which Hct in the control group was maintained in the 30 to < 33 percent range, as well as those in which Hct in the control group was maintained in the 33 to < 36 percent range.
The report addresses:
The EPC also attempted to review the outcomes of maintaining Hct above 30 percent as compared with maintaining Hct in the range 27 to < 30 percent range in pediatric CRF patients; however, no studies met the study eligibility criteria.
This systematic review addresses the following key questions.
Adult Patients with CRF
Pediatric Patients with CRF
What is the effect on outcomes of maintaining an Hct above 30 compared with 27 to < 30 percent or, maintaining Hct above 33 compared with 27 to < 33 percent?
Subpopulations of Interest (with or without CRF)
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):
It has been hypothesized that the presence of one of the conditions listed in subgroups 1 through 6 may justify maintaining Hct level above 36 percent to minimize the morbidity associated with the specified condition. For the adolescent subgroup, it is hypothesized that growth and developmental outcomes would be improved by maintaining Hct above 36 percent.
The protocol for the systematic review was prospectively designed to define: study objectives, search strategy, study selection criteria and methods for determining study eligibility, data elements to be abstracted, and methods for abstraction. Two independent reviewers completed each step in this protocol and resolved disagreements by consensus. The quality of studies was assessed qualitatively. Descriptive results are reported because the body of evidence was not suited for quantitative analysis.
The MEDLINE and EMBASE databases were searched from 1985 to December 1998 and Current Contents to October 30, 1999. Two search strategies were necessary, but both included the terms: ("erythropoietin," "epoetin alfa," "epoetin," "Epogen," "Procrit," or "epo") and ("anemia/drug therapy," "anemia/therapy," or "anemia/diet therapy"). The first strategy required the term "kidney failure" whereas the second strategy required at least one of the following terms: "heart failure," "congestive disease," "coronary disease," "arterial occlusive disease," "cerebrovascular disease," "lung diseases, obstructive;" "altitude;" or "adolescent."
Studies considered to be relevant for the second search strategy were not required to include "kidney failure." The rationale for also including studies in patients without chronic renal failure was that the clinical outcomes resulting from different levels of Hct observed in nonrenal patients with one of these clinical characteristics might be generalizable to chronic renal failure patients with the same clinical characteristic.
Thus, for example, if maintaining Hct level above 36 percent compared with 36 percent was shown to improve health outcomes in a general population of patients with peripheral vascular disease, then it might be reasonable to generalize that finding to CRF patients with peripheral vascular disease. The search results were limited to human subjects and English language literature.
The EPC included all controlled intervention studies and cross-sectional analyses that included at least 10 patients per group and that reported outcomes related to the Hct range comparisons of interest. Outcomes of interest included:
Treatment-related morbidity was assessed as well.
This review of published evidence includes both full reports and abstracts from scientific meetings. Abstracts were included in the evidence review to maximize the comprehensiveness of the evidence presented. The decision to include abstracts was made in consultation with advisory experts who suggested that the number of full reports addressing the key questions was not large and that the overall usefulness of the report would be enhanced by including analysis and synthesis of data reported in scientific abstracts. Full reports of study methodology and findings that have gone through a peer review process are viewed with greater confidence than are abstracts presented at scientific meetings.
Inherent limitations of abstracts relate primarily to the limited detail of information provided in the allowable space as well as the lack of a rigorous peer review process. Thus, results of abstracts are included to provide information of potential interest to the reader, but the evidence from abstracts would be considered preliminary and of lesser quality compared with evidence drawn from a full report.
This report has undergone extensive peer review. A Technical Advisory Group was established and served as the primary advisory panel. This group was consulted extensively through all phases of this project. In addition, the Blue Cross and Blue Shield Association Technology Evaluation Center Medical Advisory Panel, which includes nationally recognized experts in technology assessment, reviewed an early work product and provided helpful comments and analytic refinements. The National Kidney Foundation, among other national stakeholder organizations, appointed peer reviewers who provided comments on the protocol and the draft evidence report. In addition, the pharmaceutical companies who manufacture and market epoetin reviewed the draft report.
During the course of the literature review, the EPC followed the status of two additional international studies that evaluated the effects of increasing Hct above 36 percent in patients with CRF. These studies include:
At the time this systematic review was completed, results of the Canadian study had been published in two abstracts, and these findings are described in this systematic review. No results of the Scandinavian study were available.
The evidence is not sufficient to compare the outcomes of maintaining target Hct above 36 compared with maintaining the target Hct in the 33 to < 36 percent range in adults with CRF.
The evidence comparing the outcomes of maintaining target Hct above 36 percent compared with maintaining target Hct in the 33 to < 36 percent range consisted of four full reports and three abstracts. No interventional studies directly addressed this question. The main source of evidence was derived from multiple cross-sectional analyses of a large Medicare dataset consisting of over 70,000 individuals. Because Medicare reimburses for maintenance of Hct over 36 percent only for patients with a comorbid condition, the findings of such associational studies are likely to reflect the underlying comorbidity in this population. Such database analyses cannot anticipate the results of adequately controlled interventional studies where the effects of using epoetin to maintain Hct above 36 percent could be directly compared with maintaining Hct in the 33 to < 36 percent range.
The primary intent-to-treat analysis from a full report of an RCT in 1,233 hemodialysis patients with cardiac disease compared target Hct of 42 percent with target Hct of 30 percent. However, this same study reported a secondary cross-sectional analysis relating mortality to category of average achieved Hct level that specifically includes results for the 33 to 36 percent range. A full report of a Phase IV surveillance study described adverse events associated with use of epoetin and reports results for the 33 to 36 percent Hct range separately. However, all comparisons among target Hct levels were based on cross-sectional analysis, and no tests of statistical significance were reported for differences between these subgroups.
The evidence is not adequate to compare the outcomes of maintaining target Hct above 36 percent with maintaining target Hct in the 33 to < 36 percent range in adult patients with CRF. The evidence available on each of the specific outcomes of interest is summarized below.
No studies specifically compared the Hct ranges of primary interest to this systematic review with respect to the following outcomes:
The evidence is not sufficient to determine whether maintaining target Hct above 36 is more beneficial than maintaining target Hct in the 30 to < 36 percent range in adults with CRF.
Evidence comparing the outcomes of maintaining target Hct above 36 percent with the outcomes of maintaining target Hct in the > 30 to < 36 percent range consisted of 13 full reports (one full report of an RCT includes both an intent-to-treat analysis and a cross-sectional analysis) describing six interventional studies and eight cross-sectional analyses, and 10 abstracts, six interventional studies and four cross-sectional analyses. Some of these reports originated from the same authors and/or institutions, and the degree of overlap of patients across separate reports could not be determined from the information provided. Of the 12 interventional studies, only four include more than 100 patients. Two of these four were full reports and two were abstracts, both derived from the same Canadian RCT.
Additional evidence was derived from multiple cross-sectional analyses, with five of these publications, two full reports and three abstracts, coming from the same research group that analyzed a large Medicare dataset consisting of over 70,000 individuals. Because Medicare reimburses for maintenance of Hct over 36 percent only for patients with comorbid conditions, the findings of such associational studies using Medicare data are likely to reflect the underlying comorbidity in this population. One research center used an observational design to examine the natural history of predialysis patients.
Overall, the evidence is not sufficient to determine whether maintaining target Hct above 36 percent is more beneficial than maintaining target Hct in the 30 to < 36 percent range in adult patients with CRF.
Two interventional studies, both full reports, and four cross-sectional analyses, three full reports and one abstract, described mortality results. The first interventional study was an RCT of 1,233 hemodialysis patients with documented congestive heart failure or ischemic cardiac disease. This study analyzed and reported results of both an intention-to-treat analysis and a cross-sectional analysis of the data. The second interventional study was a nonrandomized controlled trial of 115 hemodialysis patients free of comorbidity. The three additional cross-sectional studies, two full reports and one abstract, analyzed large databases of patients on dialysis.
The evidence does not permit a conclusion regarding the effect on mortality of maintaining Hct above 36 percent. To date, a survival advantage has not been demonstrated.
Four interventional studies, one full report and three abstracts, and two cross-sectional studies, both full reports, described quality-of-life findings. All studies suffered from relatively weak design or methodologic flaws that might introduce biases that overestimate effect on quality of life. These data did not provide strong and consistent evidence of a benefit on quality of life of maintaining the Hct above 36 percent compared with Hct > 30 to < 36 percent.
Two interventional studies, both full reports, and four cross-sectional studies—two full reports and two abstracts—described hospital utilization. Overall, these data did not provide strong or consistent evidence of reduced hospital utilization in patients whose Hct is maintained above 36 percent as compared with those maintained at Hct > 30 to < 36 percent.
One RCT reported utilization of red blood cell transfusion. This trial of 1,233 hemodialysis patients with cardiac disease found a significant reduction in red blood cell transfusion in the normal target Hct group compared with the low target Hct group, 21 percent transfused versus 31 percent transfused, respectively (p<0.001). In this study, the need for transfusion was largely associated with acute blood loss (e.g., from gastrointestinal bleeding or as a result of surgery).
Four full reports and three abstracts discussed cardiac outcomes. Two full reports addressed cardiac clinical events, and the remainder addressed cardiac intermediate outcome measures, including left ventricular hypertrophy (LVH) (as assessed by left ventricular mass index) and left ventricular dilatation (LVD) (as assessed by left ventricular cavity volume index).
There is limited evidence on cardiac events, and the available studies are insufficient to draw conclusions. However, the evidence available does not demonstrate a reduction in cardiac events when Hct is maintained above 36 percent as compared with 30 to < 36 percent.
The evidence on cardiac intermediate outcome measures described possible relationships between Hct above 36 percent and reduced left ventricular mass and left ventricular cavity size. Two full-report cross-sectional analyses suggested an association between Hct and cardiac outcome measures. However, data were insufficient from well-designed intervention studies to determine whether raising Hct above 36 from Hct 30 to 36 percent will result in a clinically meaningful improvement in left ventricular hypertrophy.
Four small interventional studies, two full reports and two abstracts, presented findings on intermediate outcome measures related to exercise performance. The two full reports included selected patients who were free of significant cardiovascular or musculoskeletal disease; patient selection criteria were not well described in the two abstracts. No cross-sectional analyses addressed this outcome.
The available evidence is suggestive of an improvement on physiologic measures of exercise performance when Hct is maintained above 36 percent compared with Hct 30 to < 36 percent. However, whether these improvements in physiologic measures are predictive of clinically significant benefits needs to be established. In addition, such findings would need to be reproduced in large studies or populations more representative of the general population of patients with CRF.
Two full reports—one interventional study in 20 hemodialysis patients performing neurophysiologic testing and another interventional study in 10 selected hemodialysis patients evaluating sleep patterns—described testing conducted before and after Hct was raised to approximately 42 percent. A relationship between nutritional status and Hct level was described in an abstract reporting a cross-sectional analysis comparing serum levels of three different amino acids among 75 hemodialysis patients on epoetin therapy grouped according to Hct ranges. The average amino acid levels for each Hct group were compared with each other and with healthy control subjects.
Favorable results on physiologic measures of cognitive function, sleep patterns, or nutrition were observed with Hct levels above 36 percent in each of these studies. However, whether these improvements in physiologic measures are predictive of clinically significant benefits needs to be established. In addition, such findings need to be reproduced in large studies or populations more representative of the general population of patients with CRF.
Eight studies—four full reports and four abstracts—described adverse events associated with maintaining Hct above 36 percent compared with Hct > 30 to 36 percent. Seven of these were interventional studies, and one full report was a cross-sectional analysis of a Phase IV surveillance study without statistical analysis of results. Three of the four abstracts included fewer than 15 patients.
The evidence, derived from four full reports and three abstracts, showed no significant difference in overall blood pressure measurements when Hct was maintained above 36 percent compared with Hct > 30 to < 36 percent.
However, several studies suggested that some patients required intensified medical management to maintain blood pressure control at Hct above 36 percent, but these studies did not permit estimation of the magnitude of the frequency of this occurrence. An RCT in 1,233 hemodialysis patients employed well-designed concurrent controls and reported no significant differences between target Hct groups in the use of various cardiovascular medications. The listed classes of medications included several antihypertensive agents; however, the reported details of data and methods of analysis did not clarify whether medication dosage might have been increased differentially in the high target Hct group.
Five studies—two full reports and three abstracts—reported on vascular access thrombosis with Hct above 36 percent compared with Hct > 30 to < 36 percent. Targeting Hct at 42 percent significantly increased the rate of vascular access thrombosis in a population of patients with documented cardiac disease compared with targeting Hct at 30 percent. There is insufficient evidence in other groups of hemodialysis patients to determine the effect of Hct above 36 percent on vascular access thrombosis.
The evidence describing other treatment-related morbidities is limited to two full reports and one abstract. Overall, these studies did not suggest any significant increase in other adverse events such as cerebrovascular accident, transient ischemic attack, peripheral gangrene, intestinal ischemia, or seizure with Hct above 36 percent.
The evidence is not sufficient to compare the outcomes of maintaining target Hct above 30 percent with outcomes from the 27 to < 30 percent range in pediatric patients with CRF.
No studies of pediatric patients with CRF were identified that met the study selection criteria for inclusion in this systematic review. The primary reason for exclusion of most of the studies reviewed in full-text was that the baseline or control Hct with which the normalized group was being compared was below 27 percent. Thus, the available evidence does not address the key question as set out in this systematic review, particularly with regard to outcomes of treatment efficacy.
The evidence is not sufficient to determine whether target Hct above 36 percent is more beneficial than target Hct 30 to < 36 percent for subpopulations of interest with clinical characteristics thought to warrant Hct above 36 percent.
The most robust evidence on CRF patients with cardiovascular disease was from an RCT of 1,233 hemodialysis patients who had documented ischemic cardiac disease or congestive heart failure. This trial was halted because of increased mortality in the group assigned to 42 percent target Hct when compared with a 30 percent target Hct group. Although the results for a combined endpoint—death or first nonfatal MI—had not achieved statistical significance (relative risk=1.3, 95 percent CI=0.9 to 1.9), it was determined that a benefit could not be demonstrated even if the trial was completed.
A second study provided a cross-sectional analysis in patients without CRF and compared perioperative morbidity and mortality for those with or without cardiovascular disease. No statistically significant difference was seen between patients who have a preoperative Hct above 36 percent compared with those who had an Hct > 33 to < 36 percent.
A single cross-sectional analysis in patients without CRF but with cerebrovascular disease reported that, compared with patients with Hct at 30 to 35 percent, cerebral oxygen delivery was greater in those patients who had Hct levels between 40 and 45 percent, but not in those whose Hct was between 35 and 40 percent. No intervention study meeting selection criteria reported outcomes of maintaining Hct above 36 percent in a population with CRF and cerebrovascular disease.
There were no studies that met selection criteria for inclusion in this systematic review for patients who live at high altitude, who have obstructive lung disease, or who are in the adolescent age group.
The published literature does not provide strong or consistent support that maintaining Hct above 36 percent is beneficial to patients with CRF. Although limited evidence derived from physiologic measures of functional status or left ventricular mass index suggests improvements in some selected patients, the potential for benefit should be tested in well-designed intervention studies.
The published literature does not provide strong or consistent support that maintaining Hct above 36 percent is beneficial to patients with CRF. The most suggestive evidence is from studies of adult CRF patients not yet on dialysis and from studies of dialysis patients without severe comorbidity. These data are from cross-sectional analyses that show an association between higher Hct and lower left ventricular mass index.
In addition, several small intervention studies report improvement in physiologic measures of exercise performance when Hct is maintained at higher levels. The potential for benefit should be tested in well-designed intervention studies.
Well-designed, large trials that incorporate strong control measures such as masking and randomization are required to assess the outcomes of using epoetin to increase Hct above 36 percent and into the normal range, as compared with maintaining Hct in the target range recommended by the National Kidney Foundation's Dialysis Outcomes Quality Initiative (NKF-DOQI)™ of between 33 and 36 percent. The populations of primary interest are adult CRF patients not yet on dialysis and dialysis patients without overt cardiac disease (i.e., ischemia or congestive heart failure).
If benefits in physical performance, cognitive function, and prevention of cardiac disease when anemia is eliminated are confirmed in adults, it will be of utmost importance to perform similar studies in children with CRF.
The full evidence report from which this summary was derived was prepared by the Agency for Healthcare Research and Quality by the Blue Cross and Blue Shield Association Technology Evaluation Center under contract No. 290-97-0015. When available, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment No. 29, Use of Epoetin for Anemia in Chronic Renal Failure (AHRQ Publication No. 01-E016).
The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file.
AHRQ Publication Number 00-E015
Current as of August 2001
Internet Citation:
Use of Epoetin for Anemia in Chronic Renal Failure. Summary, Evidence Report/Technology Assessment: Number 29. AHRQ Publication No. 00-E015, August 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/epcrfsum.htm
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