Abstract
Background and objectives: The effects of different hemoglobin targets when using erythropoiesis-stimulating agents on quality of life are somewhat controversial, and predictors of change in quality of life in endstage renal disease have not been well characterized.
Design, setting, participants, & measurements: Five hundred ninety-six incident hemodialysis patients without symptomatic cardiac disease were randomly assigned to hemoglobin targets of 9.5 to 11.5 g/dl or 13.5 to 14.5 g/dl for 96 weeks, using epoetin_alfa as primary therapy. Patients and attending physicians were masked to treatment assignment. Quality of life, a secondary outcome, was prospectively recorded using the Kidney Disease Quality of Life (KDQoL) questionnaire at weeks 0, 24, 36, 48, 60, 72, 84, and 96, with prespecified outcomes being fatigue and quality of social interaction.
Results: The mean age and prior duration of dialysis therapy of the study population were 50.8 and 0.8 yr. Mortality was low, reflecting the relatively healthy group enrolled. Of 20 domains within the KDQoL only the prespecified domain of fatigue showed significant change over time between the two groups. Improvement in fatigue scores in the high-target group ranged from 3.2 to 7.9 over time (P = 0.007) compared with change in the low-target group. Higher body mass index and lower erythropoietin dose at baseline were independent predictors of improvement in multiple KDQoL domains.
Conclusions: In relatively healthy hemodialysis patients, normal hemoglobin targets may have beneficial effects on fatigue. Improvement in multiple domains of quality of life is associated with higher body mass index and lower erythropoietin requirements.
Anemia is highly prevalent in end-stage renal disease patients, and inadequate renal erythropoietin production is a contributing cause (1,2). Although erythropoiesis-stimulating agents have been used to treat anemia in patients with chronic kidney disease (CKD) for almost two decades, optimal hemoglobin targets remain unclear, and concerns remain about the safety of normal hemoglobin levels as a target for erythropoietin therapy. In this regard, the United States Food and Drug Administration recently issued an alert to healthcare professionals about revisions to the product label for erythropoiesis-stimulating agents in patients with chronic kidney disease (3). Notable features of this label change were the recommended hemoglobin target range of 10 to 12 g/dl and the removal of all quality of life claims, with the exception of improved exercise tolerance and functional ability.
In practice, hemoglobin levels have sometimes been maintained at levels higher than 12.0 g/dl because individual patents perceive better quality of life at higher hemoglobin levels. However, randomized trials of higher hemoglobin targets have shown heterogeneous quality of life effects. Improvements were observed in prevalent hemodialysis patients with preexisting cardiac disease (4), in Scandinavian predialysis and dialysis patients (5), and in nondialysis patients enrolled in CREATE (6), but no improvement was observed in patients enrolled in CHOIR who had less severe CKD than those in CREATE (7). In addition, the validity of quality of life findings in most of these trials is uncertain because treatment assignments were not concealed from study subjects.
We enrolled 596 incident hemodialysis patients without symptomatic cardiac disease in a randomized, controlled trial that compared a normal hemoglobin target to partial correction of anemia, with epoetin-alfa as the erythropoiesis-stimulating agent. Cardiac structure constituted the primary study outcome, and no difference was observed between the two groups (8). Clinically relevant secondary outcomes included quality of life, with prespecified outcomes being Energy/Fatigue scores and Quality of Social Interaction scores on the Kidney Disease Quality of Life (KDQoL) questionnaire and Vitality scores on the Short Form 36 (SF36) questionnaire. We have not previously reported the results from this trial of serial measurements using the KDQoL questionnaire. In this article, we examine the hypothesis that normal hemoglobin targets improve quality of life in comparatively “healthy” incident hemodialysis patients, and we also report the independent predictors of changes in the various quality of life domains assessed by the KDQoL.
Materials and Methods
Design
The design, methods and sample size assumptions of the study have been reported previously (8).
Patients were randomly assigned to one of the following hemoglobin targets: 9.5 to 11.5 g/dl (“low target”) and 13.5 to 14.5 g/dl (“high target”). Patients were masked to treatment assignment. Local investigators and the dialysis unit were also masked to treatment assignment. However, attending physicians had access to local clinic hemoglobin levels. The central coordinating centers provided treatment recommendations on erythropoietin dose, intravenous iron dose, and antihypertensive therapy for each patient (see below), but the local investigator was responsible for ordering treatment changes. Mean hemoglobin levels at the end of the initial 24-wk titration phase were 13.3 and 10.9 g/dl, respectively. During the maintenance phase, from weeks 24 to 96, corresponding mean hemoglobin levels were 13.1 and 10.8 g/dl.
Study Population
Inclusion criteria were as follows: age ≥ 18 yr, inception of maintenance hemodialysis within the previous 3 to 18 mo, predialysis hemoglobin between 8 and 12 g/dl, left ventricular volume index <100 ml/m2, and predialysis diastolic BP < 100 mmHg. Exclusion criteria were as follows: clinical evidence or history of symptomatic cardiac failure or ischemic heart disease; daily prednisone dose ≥ 10 mg; medical conditions likely to reduce epoetin responsiveness, including uncorrected iron deficiency; concurrent malignancy; blood transfusion in the preceding month; therapy with cytotoxic agents; seizure in the preceding year; hypersensitivity to intravenous iron; and current pregnancy or breastfeeding.
Description of Study Procedures
Laboratory tests were measured centrally by Quest Diagnostics (Van Nuys, CA and Heston, UK). Hemoglobin was measured weekly for 24 wk and biweekly thereafter. With the high target, the treatment goal was increments of 0.5 to 1.0 g/dl every 2 wk, until achieving stability between 13.5 and 14.5 g/dl. Other treatment goals included predialysis diastolic BP between 70 and 90 mmHg; urea reduction ratio > 67% and transferrin saturation ≥ 20%.
After random treatment assignment, patients assigned to the low target remained on their prestudy epoetin dose. Patients with the higher target received a 25% dose escalation, or an initial dose of 150 units per kilogram per week if naïve to epoetin. In both groups, when hemoglobin levels deviated from target, epoetin doses were changed by 25% of the previous dose or 25 units per kilogram. For each patient, a standardized form was faxed weekly from the study sites to the coordinating center, showing hemoglobin, epoetin dose, BP, and transferrin saturation levels. In response, treatment recommendations were faxed weekly from the coordinating center to the study sites. Initially, the choice of subcutaneous or intravenous epoetin alfa administration was discretionary; concerns about pure red cell aplasia (9) led to a study amendment on August 22, 2002, limiting administration to the intravenous route. The last patient completed the study in May 2003.
Quality of life was assessed using the KDQoL questionnaire (10), with prespecified outcomes being Energy/Fatigue scores, and Quality of Social Interaction Scores. In the original article, we reported the changes in the other prespecified outcome: Vitality scores measured using the SF36 questionnaire (8). Assessments using KDQoL were made at weeks 0, 24, 36, 48, 60, 72, 84, and 96. There was no difference in the clinical or demographic characteristics or in treatment assignment of those who had only one KDQ assessment (n = 112) and those who had serial assessments (n = 484). At each assessment, > 90% of patients remaining in the study completed the questionnaire. In a recent article, we have reported differences in transfusion rates between high and low target groups (11).
Sample Size Estimate
The sample size needed to detect a 15% difference between treatment groups in the primary outcome (left ventricular cavity volume index) was calculated as 166 per treatment group, given a two-tailed significance of 0.05, a power of 0.90, and an SD of the percentage change in left ventricular cavity volume index of 42% (8). With an expected dropout rate of 40%, primarily as a result of transplantation, 277 patients were required for each treatment group.
Analysis
Repeated measures ANOVA with mixed modeling was used to estimate time-integrated quality of life effects, over time, while simultaneously examining quality of life at each individual study assessment. Change from baseline in the high-target group compared with change from baseline in low-target group was calculated for each KDQoL domain. To identify factors predictive of changes in quality of life by domain the high- and low-target groups were combined. Repeated measures ANOVA with mixed modeling was used to estimate changes in quality of life over time. Multivariate models included target hemoglobin group, baseline hemoglobin, baseline epoetin dose, baseline transferrin saturation, age, sex, race, time on dialysis, body mass index, primary cause of renal disease, European or Canadian patients, type of vascular access and baseline serum albumin. Details of the reported model are included in Table 3. SAS, version 9.1 (SAS Institute Inc., Cary, NC) was used for data analysis.
Table 3.
Multivariate analysis of changes in quality of life: Baseline associations
| Change from Baseline
|
P1 | |||||||
|---|---|---|---|---|---|---|---|---|
| Week 24 | Week 36 | Week 48 | Week 60 | Week 72 | Week 84 | Week 96 | ||
| Burden of kidney disease | ||||||||
| female sex | 1.4 (2.0) | 1.4 (2.1) | -0.4 (2.1) | 5.2* (2.1) | -2.2 (2.2) | 0.7 (2.3) | -0.6 (2.3) | 0.02 |
| body mass index > 25.5 kg/m2 | -1.0 (2.0) | -0.8 (2.0) | 1.1 (2.0) | 0.9 (2.1) | 3.7 (2.1) | 4.6* (2.2) | 4.3 (2.2) | 0.02 |
| diabetic renal disease | 1.1 (2.7) | 7.5† (2.7) | 7.8† (2.7) | 6.7* (2.8) | 8.4† (2.9) | 5.7* (2.9) | 6.6* (2.9) | 0.01 |
| Europe | -2.4 (2.1) | -1.0 (2.1) | 3.1 (2.1) | 1.8 (2.2) | 1.8 (2.3) | 3.6 (2.3) | 3.8 (2.3) | 0.03 |
| Symptoms/problems | ||||||||
| epoetin dose > 6000 IU per week | -1.0 (1.3) | 1.6 (1.3) | 1.6 (1.3) | -1.3 (1.3) | -2.9* (1.4) | -0.4 (1.4) | -3.0* (1.4) | 0.0004 |
| body mass index >25.5 kg/m2 | -0.1 (1.2) | -1.2 (1.3) | 0.7 (1.3) | 0.5 (1.3) | 2.3 (1.3) | 2.6 (1.4) | 2.8* (1.4) | 0.01 |
| Sexual function | ||||||||
| diabetic renal disease | -2.0 (4.0) | -2.1 (4.0) | -8.3* (4.1) | -9.4* (4.2) | -6.9 (4.3) | -14.6§ (4.3) | -10.0* (4.4) | 0.008 |
| Sleep | ||||||||
| body mass index >25.5 kg/m2 | 2.2 (1.7) | -1.7 (1.7) | 0.2 (1.7) | -1.1 (1.8) | 1.3 (1.8) | 2.5 (1.8) | 3.4 (1.8) | 0.024 |
| Work status | ||||||||
| nonwhite race | -8.2 (4.3) | -6.2 (4.3) | -1.6 (4.4) | -17.9¶ (4.6) | -10.6* (4.6) | -6.2 (4.9) | -3.8 (4.7) | 0.003 |
| Overall health rating | ||||||||
| epoetin dose > 6000 IU per week | 1.9 (1.9) | 2.6 (1.9) | -0.2 (2.0) | -1.4 (2.0) | -3.7 (2.1) | -0.8 (2.1) | -1.4 (2.1) | 0.04 |
| Physical functioning | ||||||||
| age > 50.5 yr | -0.5 (2.0) | -2.7 (2.0) | -1.3 (2.0) | -4.2* (2.0) | -5.2* (2.1) | -7.0† (2.2) | -6.8† (2.2) | 0.002 |
| body mass index > 25.5 kg/m2 | -0.6 (2.0) | 0.9 (2.0) | 2.6 (2.0) | 2.0 (2.0) | 2.1 (2.1) | 5.1* (2.2) | 7.4§ (2.2) | 0.002 |
| diabetic renal disease | 0.0 (2.6) | 0.4 (2.6) | -2.6 (2.7) | -2.7 (2.7) | 2.3 (2.8) | -9.0§ (2.9) | -7.9§ (2.8) | <0.0001 |
| Role limitations-physical | ||||||||
| body mass index > 25.5 kg/m2 | -2.4 (4.4) | -2.6 (4.4) | 6.9 (4.4) | 6.1 (4.5) | 5.0 (4.7) | 8.2 (4.8) | 8.8 (4.8) | 0.028 |
| Pain | ||||||||
| epoetin dose > 6000 IU per week | -3.4 (2.7) | 0.9 (2.7) | 3.0 (2.7) | -1.0 (2.8) | -5.2 (2.9) | -1.1 (3.0) | -4.9 (2.9) | 0.027 |
| transferrin saturation ≤ 32.0% | -0.2 (2.6) | -3.2 (2.6) | -2.1 (2.7) | 5.1 (2.7) | 3.1 (2.8) | 1.5 (2.9) | 1.8 (2.9) | 0.03 |
| General health | ||||||||
| body mass index > 25.5 kg/m2 | 0.2 (1.7) | 2.2 (1.7) | 2.6 (1.7) | 0.9 (1.8) | 3.5 (1.8) | 5.3** (1.9) | 6.1** (1.9) | 0.0039 |
| Emotional well-being | ||||||||
| dialysis duration > 9.0 months | -3.9* (1.8) | 0.4 (1.8) | -2.9 (1.8) | -2.7 (1.8) | 0.6 (1.9) | -2.7 (1.9) | -2.3 (1.9) | 0.04 |
| body mass index > 25.5 kg/m2 | -2.1 (1.8) | -3.7* (1.8) | 0.1 (1.8) | -1.3 (1.8) | 0.2 (1.9) | 2.2 (1.9) | 2.6 (1.9) | 0.007 |
| diabetic renal disease | 3.9 (2.4) | 7.1** (2.4) | 5.6* (2.4) | 5.1* (2.4) | 6.9** (2.5) | 1.7 (2.6) | 4.1 (2.6) | 0.04 |
| Role limitations-emotional | ||||||||
| body mass index >25.5 kg/m2 | -4.5 (4.4) | -2.9 (4.4) | 4.1 (4.4) | 6.5 (4.5) | 4.6 (4.7) | 13.3* (4.8) | 12.1* (4.8) | 0.0002 |
| Social function | ||||||||
| body mass index >25.5 kg/m2 | 0.1 (2.4) | -1.1 (2.5) | 0.4 (2.5) | 1.0 (2.5) | 1.6 (2.6) | 8.0** (2.7) | 6.1* (2.7) | 0.004 |
| Energy/fatigue | ||||||||
| target hemoglobin 13.5 to 14.5 g/dl | 6.2* (1.9) | 5.7** (1.9) | 3.8 (1.9) | 5.3** (2.0) | 7.8*** (2.1) | 5.4* (2.1) | 3.1 (2.1) | 0.007 |
| epoetin > 6000 IU per week | 1.4 (1.9) | 2.2 (2.0) | 4.3* (2.0) | -0.4 (2.0) | -0.9 (2.1) | 1.7 (2.2) | -2.3 (2.1) | 0.028 |
| body mass index > 25.5 kg/m2 | -1.9 (1.9) | -0.8 (1.9) | 0.7 (1.9) | 0.6 (2.0) | 0.3 (2.1) | 3.3 (2.1) | 6.3*** (2.1) | 0.002 |
Repeated measures analysis of variance with mixed modeling was used to estimate changes in quality of life over time. Increasing values represent better quality of life. Parameter estimates are presented with standard errors in parentheses. Adjustment was made for target hemoglobin, hemoglobin, epoetin dose, transferrin saturation, age, sex, race, dialysis duration, body mass index, primary cause of renal disease, European or Canadian patient, vascular access for dialysis and serum albumin. The following reference groups were used: target hemoglobin 10.5 to 11.5 g/dl, hemoglobin > 11.1 g/dl, epoetin dose ≤ 6000 units per week, transferrin saturation > 32.0%, age ≤ 51.5 up years, male sex, white race, dialysis duration ≤ 9.0 months, body mass index ≤ 25.5 kg/m2, renal disease not due to diabetes, Canada, fistula or graft for dialysis access, serum albumin > 4.0 g/dl. No associations were identified for quality of social interaction, cognitive function, effects of kidney disease, dialysis staff encouragement, and patient satisfaction.
P < 0.05,
P < 0.01,
P < 0.001,
P < 0.0001 for week 24, 36, 48, 72 or 96.
Results
Five hundred ninety-six incident hemodialysis patients were enrolled in 95 treatment centers in 10 countries between February 2000 and June 2001. Table 1 compares baseline characteristics by random hemoglobin target assignment (8). Baseline characteristics were similar except for the older age of high-target subjects (52.2 versus 49.4 yr). As dictated by the study design, initial on-study epoetin doses were greater in high-target subjects (7009 versus 6183 IU per week). Also, as dictated by the study design, only patients without symptomatic heart failure or ischemic heart disease were enrolled. Eighteen percent of participants were diabetic, and median serum albumin level was 4 mg/dl. The relatively healthy group of hemodialysis patients studied was reflected in the relatively low mortality rate: 4.7 (95% confidence interval [CI] 3.0 to 7.3) per 100 patient years in the low-target group and 3.1 (1.8 to 5.4) in the high-target group, (P = 0.25).
Table 1.
Baseline characteristics of patients enrolled in this randomized trial compared by target hemoglobin level
| Characteristic | Target 9.5 to 11.5 g/dl | Target 13.5 to 14.5 g/dl | P |
|---|---|---|---|
| n | 300 | 296 | |
| Hemoglobin (g/dl) | 11.0 (10.8 to 11.1) | 11.0 (10.9 to 11.2) | 0.54 |
| Epoetin dose (IU per week) | 6183 (5698 to 6667) | 7009 (6528 to 7490) | 0.02 |
| Transferrin saturation (%) | 36.8 (34.9 to 38.8) | 35.8 (33.8, 37.7) | 0.44 |
| Age | 49.4 (47.7 to 51.2) | 52.2 (50.4 to 53.9) | 0.03 |
| Female sex (%) | 39.7 | 39.5 | 0.97 |
| Race | 0.24 | ||
| white | 87.7 | 91.2 | |
| black | 5.7 | 4.4 | |
| Asian | 4.3 | 1.7 | |
| other | 2.3 | 2.7 | |
| Dialysis duration (months) | 10.2 (9.6 to 10.8) | 10.0 (9.4 to 10.5) | 0.58 |
| Body mass index (kg/m2) | 26.3 (25.7 to 26.9) | 26.5 (25.9 to 27.1) | 0.78 |
| Country (%) | |||
| Austria | 3.0 | 4.1 | |
| Belgium | 3.3 | 4.7 | |
| Canada | 32.0 | 27.7 | |
| France | 3.0 | 2.7 | |
| Germany | 11.0 | 12.5 | |
| Greece | 2.3 | 1.4 | |
| Hungary | 10.7 | 12.2 | |
| Poland | 22.3 | 22.6 | |
| Spain | 3.0 | 3.0 | |
| United Kingdom | 9.3 | 9.1 | |
| Primary cause of renal disease | 0.54 | ||
| glomerulonephritis | 29.0 | 28.4 | |
| diabetes | 16.7 | 18.9 | |
| hypertension | 9.3 | 6.8 | |
| polycystic kidney disease | 7.7 | 10.5 | |
| Other/unknown | 37.3 | 35.5 | |
| Dialysis access (%) | 0.21 | ||
| fistula | 82.7 | 85.8 | |
| graft | 5.0 | 6.1 | |
| catheter | 12.3 | 8.11 | |
| Serum albumin (mg/dl) | 4.0 (3.9 to 4.0) | 4.0 (3.9 to 4.0) | 0.88 |
Data are reported either as percent or as means (95% confidence intervals). The chi-squared test and analysis of variance were used for between-target comparisons.
The proportions of study subjects with ≥ 1, ≥ 2, ≥ 3, ≥ 4, ≥ 5, and ≥ 6, and 7 quality of life assessments were 93.5%, 81.2%, 73.0%, 64.0%, 58.1% 47.2% and 29.3%, respectively. Table 2 shows the effect of the high hemoglobin target on KDQoL scores. Beneficial changes were seen in at least one of the seven assessments that followed randomization for nine scales. When all study assessments were considered, the high hemoglobin target had an overall, time-integrated effect on energy/fatigue and no effect on the other 19 dimensions assessed (Table 2). The improvement in Energy/Fatigue scores in the high-target group ranged from 3.2 to 7.9 over time (P = 0.007) compared with the changes in the low-target group. There was little difference in the changes of Quality of Social Interaction scores (Table 2)
Table 2.
Effect of target hemoglobin on quality of life scores
| Baseline Values
|
Change from Baseline in High Target (vs. Change from Baseline in Low Target) Week
|
P1 | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Target Hemoglobin g/dl
|
||||||||||
| 10.5 - 11.5 | 13.5 - 14.5 | 24 | 36 | 48 | 60 | 72 | 84 | 96 | ||
| Burden of kidney disease | 47.1 | 44.8 | 2.4 | 1.0 | 3.7 | 2.2 | 4.9* | 1.6 | 2.1 | 0.34 |
| (2.0) | (2.0) | (2.0) | (2.0) | (2.0) | (2.1) | (2.2) | (2.2) | (2.2) | ||
| Quality of social interaction | 66.6 | 62.8 | 0.6 | 2.9 | 0.9 | 1.4 | 0.8 | 1.9 | 1.1 | 0.76 |
| (2.2) | (2.3) | (1.7) | (1.7) | (1.7) | (1.8) | (1.8) | (1.9) | (1.9) | ||
| Cognitive function | 69.9 | 63.3 | 2.9 | 3.8* | 2.2 | 4.7** | 2.5 | 2.4 | 4.3* | 0.20 |
| (2.3) | (2.4) | (1.7) | (1.7) | (1.7) | (1.8) | (2.5) | (1.9) | (1.9) | ||
| Symptoms/problems | 80.3 | 80.0 | 0.5 | -0.5 | 0.1 | -0.3 | -0.1 | 1.3 | 0.2 | 0.91 |
| (1.0) | (1.1) | (1.2) | (1.3) | (1.3) | (1.3) | (1.30) | (1.4) | (1.4) | ||
| Effects of kidney disease | 64.6 | 65.2 | -0.2 | 1.2 | -0.7 | -0.1 | 1.7 | 1.1 | 0.5 | 0.77 |
| (1.5) | (1.5) | (1.5) | (1.5) | (1.6) | (1.6) | (1.6) | (1.7) | (1.7) | ||
| Sexual function | 69.3 | 62.3 | 2.6 | 4.5 | 5.6 | 4.4 | 6.5* | 3.1 | 5.6 | 0.54 |
| (2.6) | (2.7) | (2.9) | (3.0) | (3.0) | (3.1) | (3.2) | (3.3) | (3.3) | ||
| Sleep | 67.9 | 64.7 | -0.5 | 1.0 | -1.0 | -0.9 | -0.3 | -1.7 | -2.0 | 0.72 |
| (1.4) | (1.4) | (1.7) | (1.7) | (1.7) | (1.8) | (1.8) | (1.9) | (1.8) | ||
| Social support | 75.2 | 74.0 | 0.6 | 1.1 | 2.3 | 0.4 | 0.2 | 1.7 | -1.6 | 0.92 |
| (1.7) | (1.8) | (2.7) | (2.7) | (2.7) | (2.8) | (2.9) | (2.9) | (2.9) | ||
| Work status | 40.3 | 34.4 | 1.4 | -0.6 | 4.2 | 4.0 | 1.6 | 1.0 | 5.2 | 0.39 |
| (3.0) | (3.1) | (2.9) | (3.0) | (3.0) | (3.1) | (3.2) | (3.2) | (3.2) | ||
| Dialysis staff | 82.6 | 79.7 | 3.0 | -0.3 | 0.4 | 2.9 | 1.4 | 2.7 | 1.1 | 0.49 |
| encouragement | (1.5) | (1.5) | (2.0) | (2.0) | (2.0) | (2.1) | (2.1) | (2.2) | (2.2) | |
| Patient satisfaction rating | 75.9 | 77.3 | -0.8 | -0.2 | 0.4 | -2.6 | 0.5 | 0.1 | -1.2 | 0.76 |
| (1.5) | (1.6) | (1.9) | (1.9) | (2.0) | (2.0) | (2.1) | (2.1) | (2.1) | ||
| Overall health rating | 62.0 | 62.0 | 0.3 | 1.5 | 1.7 | 0.1 | 2.5 | 1.6 | 0.5 | 0.76 |
| (1.4) | (1.5) | (1.9) | (1.9) | (1.9) | (2.0) | (2.0) | (2.1) | (2.1) | ||
| Physical functioning | 67.1 | 62.5 | 3.1 | 4.6* | 3.5 | 4.0 | 4.4* | 5.1* | 2.4 | 0.32 |
| (1.8) | (1.9) | (2.0) | (2.0) | (2.0) | (2.1) | (2.1) | (2.2) | (2.2) | ||
| Role limitations -physical | 48.4 | 47.7 | 3.6 | 1.2 | 3.7 | 5.8 | 5.6 | 9.7* | -1.3 | 0.33 |
| (3.1) | (3.2) | (4.4) | (4.4) | (4.4) | (4.5) | (4.7) | (4.8) | (4.8) | ||
| Pain | 72.0 | 70.7 | -2.5 | 1.4 | -0.9 | -2.2 | 3.5 | 0.6 | -0.7 | 0.34 |
| (2.0) | (2.0) | (2.6) | (2.6) | (2.7) | (2.7) | (2.8) | (2.9) | (2.9) | ||
| General health | 49.4 | 48.6 | 1.3 | 1.6 | 3.2 | 1.2 | 4.0* | 1.2 | 0.6 | 0.35 |
| (1.6) | (1.6) | (1.7) | (1.7) | (1.7) | (1.8) | (1.8) | (1.9) | (1.9) | ||
| Emotional well-being | 74.0 | 67.8 | 1.7 | 2.2 | 3.9* | 2.1 | 4.5* | 2.7 | 0.7 | 0.21 |
| (1.4) | (1.6) | (1.8) | (1.8) | (1.8) | (1.8) | (1.9) | (1.9) | (1.9) | ||
| Role limitations -emotional | 68.4 | 69.1 | -3.8 | -2.1 | -1.7 | 0.4 | 0.6 | 1.3 | -0.8 | 0.95 |
| (3.0) | (3.0) | (4.4) | (4.4) | (4.4) | (4.5) | (4.7) | (4.8) | (4.8) | ||
| Social function | 74.5 | 71.4 | 2.0 | 1.2 | 3.1 | 5.8* | 4.8 | 1.1 | 1.3 | 0.25 |
| (1.7) | (1.9) | (2.4) | (2.5) | (2.5) | (2.5) | (2.6) | (2.7) | (2.7) | ||
| Energy/fatigue | 57.9 | 53.9 | 6.2** | 5.7** | 3.8* | 5.4** | 7.9*** | 5.4* | 3.2 | 0.0066 |
| (1.5) | (1.7) | (1.9) | (1.9) | (1.9) | (2.0) | (2.1) | (2.1) | (2.1) | ||
Repeated measures analysis of variance with mixed modeling was used to estimate changes in quality of life over time. Positive values represent improvements in quality of life. Parameter estimates are presented with standard errors in parentheses.
P < 0.05,
P < 0.01,
P < 0.001,
¶P < 0.0001 for the effect of target hemoglobin at week 24, 36, 48, 72, or 96.
The independent predictors of changes in quality of life for each domain were identified by combining both high- and low-target groups (Table 3). Among the covariates analyzed, no associations were identified for quality of social interaction, cognitive function, effects of kidney disease, dialysis staff encouragement, and patient satisfaction.
Older age was an independent predictor of deterioration in physical function only. Female sex was an independent predictor of increasing burden of kidney disease only. Nonwhite race was a strong predictor of not working.
Diabetes as a cause of renal disease had an independent and negative impact on sexual function and physical functioning, but was associated with improvement in scores for burden of kidney disease and emotional well being.
Higher body mass index (> 25.5) was independently predictive of improvement in scores for burden of kidney disease, symptoms/problems, sleep, physical functioning, role limitations-physical, general health, emotional well being, role limitations-emotional, social functioning, and energy/fatigue (Table 3).
High baseline erythropoietin dose (>6000 IU/wk) was a significant predictor of deterioration in scores for symptoms/problems, overall health, pain, and energy/fatigue independent of other risk factors, including target hemoglobin (Table 3).
Discussion
Randomized controlled trials comparing a normal hemoglobin target to partial corrections of anemia with epoetin have varied in the stage of CKD disease of patients enrolled, primary outcomes assessed, statistical power to compare major clinical outcomes, and research methodology. Nonetheless, signals have emerged to suggest that higher hemoglobin targets may be harmful. Clinical events related to higher hemoglobin targets in some trials have included higher vascular access thrombosis (4), higher BP or greater requirements for antihypertensives (7,8,12), cardiovascular events (4,7), earlier need for renal replacement therapy (6), and higher mortality (4,7). Adverse events for the current study were reported in the original paper, and a significantly higher number of cerebrovascular events occurred in the high hemoglobin group (n = 12) compared with the low hemoglobin group (n = 4) (8). These adverse outcomes have not been seen uniformly across studies, and several outcomes have had marginal statistical significance and wide confidence intervals for effect estimates. However higher vascular access thrombosis and hypertension have been observed in the early studies comparing no treatment of anemia with partial correction using erythropoietin (13).
Controversy exists concerning target hemoglobin levels for erythropoiesis-stimulating agent therapy in CKD. The European Medicines Agency stipulated a uniform target hemoglobin range for all patients with CKD of 10 to 12 g/dl, with a warning not to exceed a concentration of 12 g/dl (14). It noted that trials with high target hemoglobin concentrations “have not shown significant benefits attributable to the administration of epoetins to increase hemoglobin concentrations beyond the level necessary to control symptoms of anemia and to avoid blood transfusion.” However, the current study of “healthy” patients starting hemodialysis, with a sample size similar to CREATE (6), clearly demonstrates that higher hemoglobin targets reduce the need for blood transfusions (11) and produce an improvement in symptoms of fatigue. The latter is consistent with the significant improvements in vitality scores, measured by the SF36, reported in an earlier paper (8).
Although only one of 20 domains in the KDQoL and one in the SF36 showed significant improvements, these occurred in two of the three prespecified quality of life outcomes identified before starting the trial, on the basis of previous studies and biologic plausibility. Energy/fatigue scores were significantly higher in the high hemoglobin group compared with the low hemoglobin group, and the differences were of clinical significance (10,13). We compared our results to those obtained from one of the initial erythropoietin randomized controlled trials (RCTs) reported in 1990 (13). Change in baseline fatigue score at 6 mo in the group whose hemoglobin level increased from 69 to 102 g/d (n = 32) versus that of controls (n = 34) was 8, whereas in the current study the comparable change in the group whose hemoglobin level increased from 11.0 to 13.3 versus the control group was 6. Of interest, the baseline fatigue seen in the 1990 study in the intervention group was 41, and in our study it was 54, reflecting the healthier patients enrolled in the current study.
It is likely that the cost of the higher hemoglobin needed to obtain this quality of life benefit will be high (15). The improvement in quality of life observed is consistent with results in hemodialysis patients with overt cardiovascular disease (4), in Scandinavian predialysis and dialysis patients (5), and in non–dialysis-dependent CKD patients enrolled in CREATE, but is divergent from the CHOIR trial, in subjects with non–dialysis-dependent CKD (7). It should be noted however, the improvement in quality of life observed in the Besarab et al. study (4) was for improved Physical Function score in relation to achieved hematocrit.
Meta-analysis of reported RCTs conclude that normalization of hemoglobin with erythropoietin is harmful (16). We await the results of TREAT, a global RCT of 4000 predialysis diabetic patients with chronic kidney disease, planned to stop after the occurrence of 1800 cardiovascular events, to provide further evidence on the potential benefit and safety of hemoglobin targets above those currently recommended (<12 g/dl) (17). Quality adjusted costs of higher targets are extremely expensive (15). Although current international guidelines for erythropoietin therapy are justified (3,14) nonetheless, in a patient centered paradigm of care, individuals who need to avoid blood transfusions, or those at low risk of adverse outcomes who value improved energy and vitality, should not be disadvantaged by strict adherence to guidelines.
Some of the limitations of this study are worth considering. Attending physicians were masked as to assigned target hemoglobin group, but they had access to local clinic results for patient care, making it possible to unmask the assigned group. Unmasking patients to treatment assignment could influence their perceptions of quality of life. However, patients were masked, a design feature that tends to lessen the possibility that patient-related biases could explain the findings. By design, we studied hemodialysis patients without overt cardiac disease, and the generalizability of our findings to other populations with chronic kidney disease is not certain. Our results are applicable to approximately 50% of the dialysis population (18). The high dropout rate was anticipated because patients such as those in our study are usually referred for and then wait for renal transplantation. This was taken into account in the sample size estimate.
Combining both the intervention and control groups from whom serial measurements of quality of life were obtained provided a valuable resource to examine changes in quality of life in an incident cohort of hemodialysis patients. Multivariate modeling suggested that higher body mass index and lower erythropoietin dose at baseline were independent predictors of better quality of life across several domains. These predictions were independent of age, sex, diabetes mellitus, and serum albumin, and were identified in a group without symptomatic cardiac disease. Further investigation of the role of inflammation and cardiac biomarkers on quality of life is underway in this cohort, particularly because it is possible that both lower body mass index and higher erythropoietin requirements are markers for subclinical inflammation or even subclinical cardiac disease.
We conclude that in incident, relatively healthy, hemodialysis patients without symptomatic cardiac disease, normal hemoglobin targets improve energy scores. Higher body mass index and lower erythropoietin dose at baseline were independent predictors of change in several domains of quality of life.
Disclosures
P.S.P. has received research support and has been an academic advisor to companies that make erythropoietin products: Ortho Biotech, Amgen, and Roche. R.N.F. has received research support and honoraria from Ortho Biotech and honoraria from Affymax, Amgen, Ortho Biotech, and Roche. B.M.C. has received research support and honoraria from Ortho Biotech. P.S.P. declares that he had full access to all of the data in the study and had final responsibility for the decision to submit for publication.
Supplementary Material
Acknowledgments
The Canadian-European Normalization Of Hemoglobin With Erythropoietin Trial was funded by Johnson and Johnson Pharmaceutical Research and Development. The study sponsor identified the participating centers, monitored the data collection, and entered the data in a central database.
We are grateful to Janet Morgan in Canada and to Aileen Foley in England for coordinating patient enrollment and management. We are also grateful to Barbara Wittreich, Daniel Sullivan, Martin Zagari, and Dieter Frei from Ortho Biotech who made the RCT possible, and to Lou Marra from Janssen Ortho who facilitated the data transfer to the authors for the analysis in the current report.
Members of the Canadian European Study Group
EPO-INT-68 Independent Data Monitoring Committee Members:
L.J. Wei, Boston, MA; M.-M. Samama, Paris, France; P. Ivanovich, Chicago, IL; M.A. Pfeffer, Boston, MA
Principal Investigator/Site: W. Hoerl, Wien, Austria; H.-K. Stummvoll, Linz, Austria; G. Mayer, Innsbruck, Austria; H. Graf, Wien, Austria; H. Holzer, Graz, Austria; Y. Vanrenterghem, Leuven, Belium; M. Jadoul, Belgium; P. Parfrey, St. John's, Canada; P. Barre, Montréal, Canada; A. Levin, Vancouver, Canada; P. Cartier, Montréal, Canada; N. Muirhead, London, Canada; A. Fine, Winnipeg, Canada; B. Murphy, Calgary, Canada; S. Handa, St. John's, Canada; P. Campbell, Edmonton, Canada; V. Pichette, Montréal, Canada; S. Tobe, Toronto, Canada; C. Lok, Toronto, Canada; D. Kates, Kelowna, Canada; D. Holland, Kingston, Canada; G. Karr, Penticton, Canada; G. Pylpchuk, Saskatoon, Canada; G. Wu, Mississauga, Canada; M. Vasilevsky, Montréal, Canada; E. Carlisle, Hamilton, Canada; E.R. Gagne, Fleurimont, Canada; W. Callaghan, Windsor, Canada; G. Soltys, Greenfield Park, Canada; P. Tam, Scarborough, Canada; R. Turcot, Trois-Rivieres, Canada; M. Berrall, Toronto, Canada; J. Zacharias, Winnipeg, Canada; S. Donnelly, Toronto, Canada; G. London, Fleury-Merogis, France; A. London, Aulnay sous Bois, France; F.P. Wambergue, Lille, France; H. Geiger, Frankfurt, Germany; V. Kliem, Hann Muenden, Germany; R. Winkler, Rostock, Germany; B. Kraemer, Regensburg, Germany; H. Schiffl, Munich, Germany; R. Brunkhorst, Hanover, Germany; D. Seybold, Bayreuth, Germany; M. Hilfenhaus, Langenhagen, Germany; D. Schaumann, Hameln, Germany; R. Goetz, Bad Windsheim, Germany; P. Roch, Regensburg, Germany; H.-P. Brasche, Ludwigshafen, Germany; V. Wizemann, Giessen, Germany; K. Bittner, Ansbach, Germany; K. Appen, Hamburg, Germany; B. Schroeder, Bad Toelz, Germany; W. Schropp, Munich, Germany; D. O'Donoghue, Salford, England; I. MacDougall, London, England; G. Warwick Leicester, England; M. Raftery, London, England; K. Farrington, Stevenage, England; J. Kwan, Carshalton, England; P. Conlon, Dublin, Ireland; G. Mellotte, Dublin, Ireland; K. Siamopoulos, Ioannina, Greece; N. Tsaparas, Crete, Greece; D. Tsakiris, Veria, Greece; V. Vargemezis, Alexandroupolis, Greece; S. Ferenczi, Gyor, Hungary; S. Gorogh, Kisvarda, Hungary; I. Kulcsar, Szombathely, Hungary; L. Locsey, Debrecen, Hungary; K. Akocsi, Veszprem, Hungary; I. Solt, Szekesfehervar, Hungary; O. Arkossy, Budapest, Hungary; E. Kiss, Szeged, Hungary, J. Manitius, Bydgoszcz, Poland; B. Ruthowski, Gdansk, Poland; A. Wiecek, Katowice, Poland; W. Sulowicz, Krakow, Poland; A. Ksiazek, Lublin, Poland; S. Czekalski, Poznan, Poland; M. Klinger, Wroclaw, Poland; M. Mysliwiec, Bialystok, Poland; H. Augustyniak-Bartosik, Milicz, Poland; M. Imiela, Warszawa-Miedzylesie, Poland; A. Sydor, Tarnow, Poland; R. Rudka, Bytom, Poland; M. Kiersztejn, Chrzanow, Poland; R. Wnuk, Oswiecim, Poland; A. Milkowsk, Krakow, Poland; F. Valderrabano, Madrid, Spain; P. Aljama, Córdoba, Spain; H. Alcocer, Valencia, Spain; A. Purroy, Pamplona, Spain.
Published online ahead of print. Publication date available at www.cjasn.org.
References
- 1.Higgins MR, Grace M, Ulan RA, Silverberg DS, Bettcher KB, Dossetor JB. Anemia in hemodialysis patients. Arch Intern Med 137: 172-176. 1977 [PubMed] [Google Scholar]
- 2.Goodnough LT, Monk TG, Andriole GL: Erythropoietin therapy. N Engl J Med 336: 933-938. 1997 [DOI] [PubMed] [Google Scholar]
- 3. Follow Up to the January 3, 2008 Communication About an Ongoing Safety Review Erythropoiesis-Stimulating Agents (ESAs) Epoetin alfa (marketed as Procrit, Epogen) Darbepoetin alfa (marketed as Aranesp). http://www.fda.gov/cder/drug/infopage/RHE. Accessed March 2008
- 4.Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339: 584-590, 1998 [DOI] [PubMed] [Google Scholar]
- 5.Furuland H, Linde T: Ahlmen J, Christensson A, Strombom U, Danielson BG: A randomized controlled trial of hemoglobin normalization with epoetin alfa in predialysis and dialysis patients. Nephrol Dial Transplant 18: 353-361, 2003 [DOI] [PubMed] [Google Scholar]
- 6.Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355: 2071-2084, 2006 [DOI] [PubMed] [Google Scholar]
- 7.Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355: 2085-2098, 2006 [DOI] [PubMed] [Google Scholar]
- 8.Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D: Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 16: 2180-2189, 2005 [DOI] [PubMed] [Google Scholar]
- 9.Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 346: 469-4675, 2002 [DOI] [PubMed] [Google Scholar]
- 10.Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB: Development of the Kidney Disease Quality of Life (KDQOL) instrument. Qual Life Res 3: 329-338, 1994 [DOI] [PubMed] [Google Scholar]
- 11.Foley RN, Curtis BM, Parfrey PS: Hemoglobin targets and blood transfusion rates in hemodialysis patients without symptomatic cardiac disease receiving erythropoietin therapy. Clin J Am Soc Nephrol 3: 1969-1975, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Foley RN, Parfrey PS, Morgan J, Barré PE, Campbell P, Cartier P, Coyle D, Fine A, Handa P, Kingma I, Lau CY, Levin A, Mendelssohn D, Muirhead N, Murphy B, Plante RK, Posen G, Wells GA: Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 58: 1325-1335, 2000 [DOI] [PubMed] [Google Scholar]
- 13.Canadian Erythropoietin Study Group: Associated between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ 300: 573-578, 1990 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.European Medicines Agency: Public Statement: Epoetins and the Risk of Tumour Growth Progression and Thromboembolic Events in Cancer Patients and Cardiovascular Risks in Patients with Chronic Kidney Disease. Available at: http://www.emea.europa.eu/pdfs/human/press/pus/49618807en.pdf. Accessed March 2008
- 15.Tonelli M, Winkelmayer WC, Jindel KK, Owen WF, Manns BJ: The cost-effectiveness of maintaining higher hemoglobin targets with erythropoietin in hemodialysis patients. Kidney Int 64: 295-304, 2003 [DOI] [PubMed] [Google Scholar]
- 16.Phrommintikul A, Haas SJ, Elsik M, Krum H: Mortality and target hemoglobin concentrations in anemic patients with chronic kidney disease treated with erythropoietin: A meta-analysis. Lancet 369: 381-388, 2007 [DOI] [PubMed] [Google Scholar]
- 17.Mix TC, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS, McGill JB, McMurray JJ, Parfrey PS, Parving HH, Pereira BJ, Remuzzi G, Singh AK, Solomon SD, Stehman-Breen C, Toto RD, Pfeffer MA: Rationale –Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): Evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J, 149: 408-413, 2005 [DOI] [PubMed] [Google Scholar]
- 18.Murphy SW, Foley RN, Barrett BJ, Kent GM, Morgan J, Barre P, Campbell P, Fine A, Goldstein MB, Handa SP, Jindal KK, Levin A, Mandin H, Muirhead N, Richardson RM, Parfrey PS: Comparative mortality of hemodialysis and peritoneal dialysis in Canada. Kidney Int 52: 1720-1726, 2000 [DOI] [PubMed] [Google Scholar]
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