Clinical Dialysis

Double-Blind Comparison of Full and Partial Anemia Correction in Incident Hemodialysis Patients without Symptomatic Heart Disease

Patrick S. Parfrey, Robert N. Foley, Barbara H. Wittreich, Daniel J. Sullivan, Martin J. Zagari, Dieter Frei and ; for the Canadian European Study
JASN July 2005, 16 (7) 2180-2189; DOI: https://doi.org/10.1681/ASN.2004121039

Abstract

It is unclear whether physiologic hemoglobin targets lead to cardiac benefit in incident hemodialysis patients without symptomatic heart disease and left ventricular dilation. In this randomized, double-blind study, lower (9.5 to 11.5 g/dl) and higher (13.5 to 14.5 g/dl) hemoglobin targets were generated with epoetin α over 24 wk and maintained for an additional 72 wk. Major eligibility criteria included recent hemodialysis initiation and absence of symptomatic cardiac disease and left ventricular dilation. The primary outcome measure was left ventricular volume index (LVVI). The study enrolled 596 patients. Mean age, duration of dialysis therapy, baseline predialysis hemoglobin, and LVVI were 50.8 yr, 0.8 yr, 11.0 g/dl, and 69 ml/m2, respectively; 18% had diabetic nephropathy. Mean hemoglobin levels in the higher and lower target groups were 13.3 and 10.9 g/dl, respectively, at 24 wk. Percentage changes in LVVI between baseline and last value were similar (7.6% in the higher and 8.3% in the lower target group) as were the changes in left ventricular mass index (16.8 versus 14.2%). For the secondary outcomes, the only between-group difference was an improved SF-36 Vitality score in the higher versus the lower target group (1.21 versus −2.31; P = 0.036). Overall adverse event rates were similar in both target groups; higher (P < 0.05) rates of skeletal pain, surgery, and dizziness were seen in the lower target group, and headache and cerebrovascular events were seen in the higher target group. Normalization of hemoglobin in incident hemodialysis patients does not have a beneficial effect on cardiac structure, compared with partial correction.

Left ventricular hypertrophy (LVH) is present in nearly 80% of dialysis patients (1). Morphologically, left ventricular dilation and concentric hypertrophy are approximately equally represented, and both conditions are associated with higher rates of cardiovascular events (1–7). In dialysis patients, anemia is associated with LVH, left ventricular dilation, congestive heart failure, hospitalization, and mortality (8–11). Controlled studies with quality of life (QOL) and left ventricular mass as end points support partial correction of hemoglobin in dialysis patients (12–14). These findings underpin guidelines from the United States, Europe, and Canada, which suggest hemoglobin levels between 11 and 12 g/dl in dialysis patients (15–17). The potential risks and benefits of higher hemoglobin targets in dialysis patients have generated considerable discussion. Evaluation of studies reported to date (18–21), with the benefit of hindsight, led to concerns in one or more of the following areas: Late intervention, small sample size, short follow-up, and nonblinded participants. The current study was conducted to compare the impact of higher versus lower hemoglobin targets on left ventricular size in incident hemodialysis patients without symptomatic cardiac disease. Secondary outcomes included left ventricular mass index (LVMI), 6-min walking test, QOL, and the occurrence of adverse events.

Materials and Methods

Among incident hemodialysis patients without symptomatic cardiac disease and left ventricular dilation, we compared the effects of higher (13.5 to 14.5 g/dl) and lower (9.5 to 11.5 g/dl) hemoglobin targets maintained with epoetin α on (1) left ventricular volume index (LVVI), the primary outcome; (2) LVMI; (3) the incidence of de novo congestive heart failure; (4) QOL, as revealed by vitality, fatigue, and quality of social interaction scores; and (5) 6-min walking test performance.

Study Population

Adult (≥18 yr of age) hemodialysis patients were selected using the following inclusion criteria: (1) Predialysis hemoglobin between 8 and 12 g/dl; (2) hemodialysis started in the preceding 3 to 18 mo (this relatively broad definition for early intervention was chosen to facilitate enrollment); (3) LVVI <100 ml/m2 on screening echocardiography, with normal being <90 ml/m2; and (4) predialysis diastolic BP <100 mmHg. The exclusion criteria were (1) symptomatic ischemic heart disease or heart failure; (2) angiographic critical coronary artery disease; (3) current treatment ≥10 mg of prednisone daily for a failed renal transplant; (4) surgery for pericardial or valvular disease within the last 2 yr; (5) medical conditions that are likely to reduce the response to epoetin α, including uncorrected iron deficiency; (6) concurrent malignancy; (7) blood transfusion within the preceding month; (8) therapy with cytotoxic agents; (9) seizure within the previous year; (10) hypersensitivity to intravenous iron; and (11) current pregnancy or breastfeeding.

Design

A randomized, double-blind design was used with patients and outcome assessors but not treating physicians, who were blinded to assigned hemoglobin target. The study was divided into a 24-wk titration phase, which was used to achieve hemoglobin targets, and a 72-wk maintenance period.

Local independent ethics committees or institutional review boards approved the study protocol form before study initiation. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients gave informed consent before study enrollment.

Study Procedures

The study was centrally monitored from St. John’s, Canada (P.S.P.), for Canadian patients and Manchester, England (R.N.F.), for European patients. Thirty percent of patients enrolled were from Canada, and 70% were from Europe. Screening echocardiograms were sent to a central site (Cardialysis B.V., Rotterdam, The Netherlands) to determine whether LVVI was <100 ml/m2. Randomization was performed at the two coordinating centers with an interactive voice randomization telephone system, using permuted blocks, stratified by gender and concurrent epoetin use.

Laboratory tests were measured by Quest Diagnostics (Van Nuys, CA, and Heston, UK). Baseline evaluations included medical history, vital signs, height and weight, blood chemistry, M-mode echocardiography, electrocardiography, Kidney Disease Quality of Life (KDQOL) (22), Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale (23), and a 6-min walking test (24). As part of the sponsor’s effort to investigate the occurrence of pure red-cell aplasia in patients who received epoetin α, the protocol was amended after 36 mo to mandate measurement of anti-erythropoietin antibodies and serum erythropoietin.

The following treatment targets were used: (1) Predialysis hemoglobin levels of 9.5 to 11.5 g/dl throughout in the lower target group and, in the higher target group, increments of 0.5 to 1.0 g/dl biweekly, until achieving stability between 13.5 and 14.5 g/dl (measured weekly for 24 wk, then biweekly); (2) predialysis diastolic BP between 70 and 90 mmHg (measured weekly for 24 wk, then every 4 wk); (3) urea reduction ratio >67% (measured every 4 wk for 24 wk, then every 12 wk); and (4) transferrin saturation ≥20% (measured biweekly for 24 wk, then every 4 wk).

Between February 2000 and June 2001, 596 patients were enrolled in 95 treatment centers in 10 European countries and Canada. For each patient, a form was faxed weekly to the coordinating center displaying hemoglobin, epoetin α regimen, BP, and transferrin saturation levels. Treatment recommendations were faxed back, weekly. Initially, epoetin α could be administered subcutaneously or intravenously. A study amendment, effective August 22, 2002, limited administration to the intravenous route. The last patient completed the study in May 2003.

A predefined algorithm was used for epoetin α therapy. Epoetin-naïve patients in the higher target group were assigned a dose of 150 IU/kg per wk. For hemoglobin levels that deviated from target, epoetin doses were changed by 25% of the previous dose or 25 IU/kg.

Outcome Measures

Echocardiograms were performed at 24, 48, and 96 wk after study start. Standard echocardiographic recordings were performed within 1 kg of dry weight, usually within 24 h after the midweek dialysis. Dry weight was the optimal postdialysis weight for BP control without symptoms of blood volume contraction. American Society of Echocardiography criteria (25) were used, and echocardiograms were read by an independent central reader, Cardialysis. Left ventricular volume, in milliliters, was calculated as 0.001047 (left ventricular end-diastolic diameter mm)3 (26). Left ventricular mass, in grams, was calculated as 0.00083 × [(end-diastolic diameter mm + interventricular septum thickness mm + posterior wall thickness mm)3 − (end-diastolic diameter mm)3 + 0.6] (27). LVVI and LVMI were calculated as left ventricular volume/M2 body surface area and left ventricular mass/M2 body surface area, respectively (28).

The 6-min walking test was performed at 24, 48, and 96 wk after study start, and QOL scales were recorded at 24, 36, 48, 60, 72, 84, and 96 wk. The FACIT fatigue scale and two subscales from the KDQOL, the SF-36 Vitality and KDQOL Quality of Social Interaction, were chosen for analysis before initiating the study, with higher values representing better QOL. The 6-min walking test measured the distance walked in 6 min, change in heart rate from pre- to postexercise, and perceived exertion (24). De novo heart failure was defined as dyspnea at rest with two of the following: Increased jugular venous pressure, bilateral basal crackles, radiographic pulmonary hypertension, and radiographic interstitial edema. Safety evaluations included adverse events as defined by the investigator, vital signs, and laboratory measures.

Statistical Analyses

Data from Canadian Normalization of Hemoglobin trial were used to guide sample size estimation (19). The sample size needed to detect a 15% difference between treatment groups 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%. With an expected dropout rate of 40%, primarily as a result of transplantation, 277 patients were required for each treatment group.

The intention-to-treat philosophy was used. Analysis of covariance (adjusted for age, epoetin use at randomization, and baseline LVH) was used to adjust the effect of hemoglobin target on percentage change in LVVI and LVMI. De novo heart failure rates were compared using time-to-event analyses. QOL outcomes were compared in patients with at least one QOL score, using piecewise linear regression, where QOL growth curves were allowed to change slopes at week 24, i.e., one slope was used from weeks 0 to 24, and another slope was used from week 24 and beyond. The main QOL analysis assumed that missing QOL data were missing at random; however, a sensitivity analysis, which did not assume that data were missing at random, yielded similar findings. The primary QOL assessment was mean follow-up minus baseline QOL score, with P values adjusted for multiple comparisons using the Hochberg procedure (29).

The proportions with at least one treatment-emergent adverse event were compared by treatment assignment; because the number of component conditions was very large, any adverse event that occurred in >10% of patients is reported here, as are vascular events, access loss events, cardiac events, and death when the occurrence rates exceeded 2%. Parametric, two-sided statistical tests were used throughout, with a type I error of 0.05, using SAS Version 6.12.

Role of the Funding Source

The study sponsor, Johnson & Johnson Pharmaceutical Research and Development, LLC, identified the participating centers, monitored the data collection, and entered the data in a central database.

Results

Patients

Baseline characteristics of the 596 patients enrolled are shown in Table 1 and were similar in the two randomly assigned treatment groups, apart from age, which was greater in the higher target group. As anticipated, 324 (54%) patients remained in the study for 96 wk, 160 (54%) in the higher and 164 (55%) in the lower target groups. The reasons for study exit—renal transplantation (n = 133, 67 in the higher and 66 in the lower target group), adverse events (n = 76, 39 and 37), patient choice (n = 28, 9 and 19), loss to follow-up (n = 2, 1 and 1), and other (n = 36, 21 and 15)—were similar in the two target groups. The mean times in the study were similar for both target groups: 73.4 ± 31.1 wk for the higher compared with 74.0 ± 31.8 for the lower target group. In total, 339 patients had echocardiograms performed after 72 wk of follow-up.

View this table:
Table 1.

Baseline characteristics for the lower and higher target groupsa

Figure 1 shows hemoglobin levels and epoetin α doses in the two target groups. Toward the end of the titration phase, at 24 wk, the mean hemoglobin levels in the higher and lower target groups were 13.3 ± 1.5 and 10.9 ± 1.2 g/dl, respectively. During the maintenance phase, from weeks 24 to 96, mean hemoglobin levels were 13.1 ± 0.9 g/dl in the higher and 10.8 ± 0.7 g/dl in the lower target group. Predialysis hemoglobin levels, averaged for the whole study, including both the titration and the maintenance phases, were 12.6 ± 1.0 g/dl in the higher and 10.9 ± 0.7 g/dl in the lower target group, whereas the corresponding postdialysis levels were 13.5 ± 1.2 and 11.8 ± 1.1 g/dl, respectively. The proportionate increase in post- to predialysis hemoglobin, which reflects interdialytic weight gain, were similar in both groups (7 versus 8%).

Figure 1.
Figure 1.

Hemoglobin levels (top) and epoetin α doses (bottom), presented as means ± 2 SE in the higher and lower target groups.

Table 2 summarizes clinical indicators at the beginning and at the end of the study. The last observed values were similar in the two target groups except for a higher proportion receiving intravenous iron, number of antihypertensive drugs, and lower urea reduction ratios in the higher target group (all P < 0.05). There was no difference in the change in number of antihypertensive drugs from baseline to last value, comparing the two groups.

View this table:
Table 2.

Clinical indicators for the lower and higher target groups

Table 3 shows the major cardiac outcomes of the study, compared by assigned hemoglobin target. LVVI did not change significantly over time in the overall study population, and changes in LVVI were similar in both target groups. Although LVMI increased over time in the overall study population (P < 0.001), the changes observed were unaffected by target hemoglobin assignment. These conclusions were unchanged when only those who had echocardiogram performed after week 80 were included in the analysis. Rates of de novo heart failure were similar in both target groups, as were the changes in 6-min walking distance.

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Table 3.

Changes in LVVI, LVMI, 6-min walking test, and incidence of heart failure for the lower and higher target groupsa

Table 4 shows the QOL outcomes, by assigned hemoglobin. SF-36 Vitality scores improved more in the higher than in the lower target group (P = 0.036), and differences between target groups, adjusted for multiple comparisons, were significant at weeks 24, 36, 48, 60, and 72 (Figure 2). No significance between-group differences were seen in the time course of FACIT Fatigue scores and the KDQOL Quality of Social Interaction scores.

Figure 2.
Figure 2.

Mean of change in SF-36 Vitality scores from baseline in the lower and higher target groups, presented ± 2 SE. *P < 0.05.

View this table:
Table 4.

Quality-of-life outcomes for the lower and higher target groupsa

Thirty-three patients, 20 in the lower and 13 in the higher target group, died during the study (P = 0.28). Table 5 shows rates of treatment-emergent adverse events, vascular events, access loss events, cardiac events, and death. The proportions with at least one treatment-emergent adverse event were similar in both target groups; more patients in the lower target group experienced skeletal pain (P = 0.009), surgery (P = 0.013), and dizziness (P = 0.001), whereas more patients in the higher target group experienced headache (P = 0.030) and cerebrovascular events (P = 0.045).

View this table:
Table 5.

Treatment-emergent adverse events that occurred in ≥10% of patients; vascular, access loss, and cardiac events that occurred in ≥2% of patients; and death in lower and higher target groupsa

Discussion

We studied patients who had recently started hemodialysis therapy without overt cardiac disease. The fraction of incident dialysis patients in the Canadian echocardiographic cohort study (1), with manifestations similar to the inclusion criteria of the current study (no symptomatic heart failure or ischemic heart disease and LVVI < 100 ml/m2) was 43%. Hemoglobin targets higher than the current guidelines had no effect on cardiac dimensions, the incidence of congestive heart failure, or performance on a 6-min walking test. QOL (in terms of vitality) was improved. Adverse event rates were comparable in both groups, except for skeletal pain, surgery, and dizziness being significantly higher in the lower target group and headaches and cerebrovascular events being higher in the higher target group.

Several observational studies have shown associations between anemia and adverse outcomes in dialysis patients (8–11). Both uncontrolled (30,31) and controlled (14) studies have shown that partial correction of anemia leads to partial regression of LVH in dialysis patients, in addition to improving QOL and physical performance (12,13). Three controlled studies of normalization of hemoglobin with erythropoietin in hemodialysis populations have been reported to date. The United States Normal Hematocrit Trial differed from our study in several respects, including the requirement of pre-existing symptomatic cardiac disease, a higher proportion of patients with diabetes, patients on dialysis therapy an average of 3 yr or more, the predominance of synthetic grafts for vascular access, and the administration of substantially larger epoetin α doses in both target groups. Primary outcome rates (death or first nonfatal myocardial infarction) were higher in the higher target groups, although this was not statistically significant. Although rates of access loss were significantly higher in the normalized group, QOL was better (18). The study was stopped early because of significantly higher rates of vascular access thrombosis and loss, together with 30% higher mortality in the high hematocrit group. The Canadian Normalization of Hemoglobin trial included patients with asymptomatic LVH or LV dilation. The higher hemoglobin target failed to induce regression of pre-existing LVH or dilation. Secondary outcome analysis suggested that higher hemoglobin levels could prevent de novo left ventricular dilation; in addition, QOL was improved without compromising vascular access (arteriovenous fistulas, predominantly) (19). Another study used a double-blind crossover design to compare hemoglobin targets of 10 and 14 g/dl, each applied for 6 wk; the higher target led to reduced cardiac output and improved QOL (21).

Two trials of higher hemoglobin targets, not restricted to hemodialysis patients, have been reported. A Scandinavian study with target hemoglobin levels of 9.0 to 12.0 or 13.5 to 16.0 g/dl included dialysis and nondialysis patients with chronic kidney disease. QOL improved with the higher target, whereas thrombovascular event rates, including those involving vascular access, were similar (20). An Australian study compared strategies of early or delayed anemia therapy targets in patients with chronic kidney disease. Eligible patients had hemoglobin levels of 11.0 to 12.0 g/dl (women) or 11.0 to 13.0 g/dl (men). One group received epoetin α immediately, to maintain hemoglobin between 12.0 and 13.0 g/L. In the other group, hemoglobin was allowed to decline below 9.0 g/dl; epoetin α then was used to maintain levels between 9.0 and 10.0 g/dl. The mean hemoglobin levels achieved, in practice, were 12.1 and 10.8 g/dl, respectively. In this 2-yr study, changes in LVMI were similar in both target groups (32). Thus, the available literature suggests, as in our study, that enhanced QOL is the only consistent benefit conferred by normalizing hemoglobin in patients with chronic kidney disease.

Assessment of different adverse event rates should take account of the fact that multiple comparisons were made. The observation that a higher number of cerebrovascular events occurred in the higher (n = 12) compared with the lower (n = 4) target group requires further study. Previous trials in chronic kidney disease did not report a higher incidence of stroke in the higher target group (18–21), but concern has been expressed regarding thrombotic events during erythropoietin therapy in oncology studies (33). The higher cerebrovascular event rate was not supported by a higher death rate in the higher target (n = 13) compared with the lower (n = 20) target group, and other cardiovascular events rates were similar. The BP levels were similar in both groups. Although a higher number of antihypertensive agents were prescribed in the higher group (compared with the lower group) at study end, the change in number of antihypertensive agents from baseline was similar in both groups.

Certain limitations in our study need to be considered. (1) The study was not powered to examine major cardiovascular events and death. This being said, our study used a randomized, double-blind design; a reasonable duration of follow-up; and sequential measurements in an incident cohort that started hemodialysis. (2) The positive findings of our study—that higher hemoglobin levels increase vitality—were generated from secondary outcome analyses. The changes observed were probably clinically important (34). (3) Our study, by design, selected hemodialysis patients without symptomatic cardiac disease and severe left ventricular dilation, and its findings can be truly generalized only to such patients (approximately 40 to 50% of incident dialysis patients). As a result of the inclusion criteria, the average age of the patients studied (51 yr) was younger than the median age of incident patients in Canada in 2000 (65 yr), and the proportion with diabetes (18%) was lower (44%) (35). This is reflected in the low mortality rate during the study (5.5%). (4) Despite central monitoring with real-time treatment recommendations, we approached but failed to reach intended hemoglobin targets in the higher target group. However, the separation by target group was approximately 2.3 g/dl throughout the maintenance phase of the study and was compatible with the sample size assumption that a 15% difference in LVVI changes would be associated with a 2-g/dl difference in hemoglobin levels (19). Therefore, it seems unlikely that the failure to achieve hemoglobin targets could fully account for the similarity seen in the primary outcome comparisons. (5) Although we observed no difference in cardiovascular, access, and malignancy rates, the actual event rates were low, and an untreated placebo group was not used. Thus, small or moderate differences in event rates cannot be excluded. (6) The high dropout rate was anticipated because patients such as those in our study are usually referred and then wait for renal transplantation. No differences in the primary outcome were observed whether analyzed by changes from baseline to last value or by analysis of serial measurements.

Despite its limitations, we believe that this randomized, controlled trial, in enrolling a large number of incidence hemodialysis patients, in achieving a clinically important difference in hemoglobin levels, and in serial follow-up of several clinically important outcomes over 2 yr, provides important information regarding the question of normalizing hemoglobin in dialysis patients. It suggests that normalization of hemoglobin in patients who start hemodialysis, although improving vitality, has no effect on left ventricular size when compared with patients who are maintained with hemoglobin levels between 9.5 and 11.5 g/dl.

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, Belgium; W. Lornoy, Aalst, Belgium; C. Tielemans, Bruxelles, Belgium; M. Jadoul, Bruxelles, 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, Montreal, 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, Montreal, Canada; E. Carisle, Hamilton, Canada; E.R. Gagne, Fleurimont, Canada; W. Callaghan, Windsor, Canada; G. Soltys, Greenfield Park, Canada; P. Tam, Scarborough, Canada; R. Turcot, Trios-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, Hannover, 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. Rutkowski, 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; J. 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

Acknowledgments

This paper was presented at the American Society of Nephrology Clinical Trials Symposium, November 1, 2004, St. Louis, MO (J Am Soc Nephrol 15: 726A, 2004).

We are grateful to Janet Morgan in Canada and to Aileen Foley in England for coordinating patient enrollment and management.

P.S.P. and R.N.F., the co-principal investigators, designed the trial, applied for funding to Johnson and Johnson, coordinated the study, and wrote the report. D.J.S. performed the statistical analyses and contributed to preparation of the manuscript. B.H.W. contributed to the study design, collection of data, and preparation of the manuscript. M.J.Z. contributed to the study design with respect to QOL analysis, to analysis and interpretation of the data, and to the manuscript. D.F. contributed to the study design, to the collection and analysis of the data, and to the manuscript.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • Conflict of interest statement: P.S.P. has received research support and is an academic advisor to companies that make erythropoietin products—Ortho Biotech, Amgen, and Roche. 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. R.N.F. has received research support and honoraria from Ortho Biotech. D.J.S. is an employee of Johnson & Johnson. B.H.W., M.J.Z., and D.F. are employees of Ortho Biotech.

    P.S.P. and R.N.F. contributed equally to this work.

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Double-Blind Comparison of Full and Partial Anemia Correction in Incident Hemodialysis Patients without Symptomatic Heart Disease
Patrick S. Parfrey, Robert N. Foley, Barbara H. Wittreich, Daniel J. Sullivan, Martin J. Zagari, Dieter Frei
JASN Jul 2005, 16 (7) 2180-2189; DOI: 10.1681/ASN.2004121039
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