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Dialysis patients treated with Epoetin alpha show improved exercise tolerance and physical function: A new analysis of the Canadian Erythropoietin Study Group trial
Muirhead N, Keown PA, Churchill DN, Poulin-Costello M, Gantotti S, Lei L, Gitlin M, Mayne TJ
Hemodialysis International. 2011;15((1):):87-94.
Abstract
The risks/benefits of anemia treatment in dialysis patients have been redefined in the US Epoetin alpha label. This analysis was carried out to determine if increasing hemoglobin (Hb) levels improve exercise tolerance and physical function in anemic dialysis patients. This is a new analysis of the Canadian Erythropoietin Study Group trial, a double-blind, randomized, placebo-controlled trial in dialysis patients. Subjects were 18 to 75 years old, on hemodialysis for >3 months, and had a baseline Hb <9.0g/dL. Patients with a history of diabetes mellitus, ischemic heart disease, or severe/uncontrolled hypertension were excluded. Patients were randomized to receive Epoetin alpha to a target Hb of 9.5 to 11.0g/dL (n=40) or a target of 11.5 to 13.0g/dL (n=38), or receive placebo (n=40). Results from patients in the Epoetin-alpha-treated arms were combined for this analysis. Hb level, exercise tolerance (Treadmill Stress Test and 6-Minute Walk Test) and patient-reported physical function measures (Physical Summary domain from the Kidney Disease Questionnaire, and 4 domains from the Sickness Impact Profile) were reported at baseline and months 2, 4, and 6. Differences in measures were statistically significant for exercise tolerance (Treadmill Stress, P=0.0001) and patient-reported physical function (Kidney Disease Questionnaire Physical, P=0.0001; Sickness Impact Profile Physical, P=0.0015) across all time points for Epoetin-alpha-treated patients compared with placebo. Improvements were seen at 2 months and were maintained through months 4 and 6. Dialysis patients receiving Epoetin alpha showed improved exercise tolerance and physical function. These findings should be considered as physicians weigh the risks and benefits of treatment. 2010 The Authors. Hemodialysis International 2010 International Society for Hemodialysis
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Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD
Levin A, Djurdjev O, Thompson C, Barrett B, Ethier J, Carlisle E, Barre P, Magner P, Muirhead N, Tobe S, et al
American Journal of Kidney Diseases. 2005;46((5):):799-811.
Abstract
BACKGROUND This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data. METHODS One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12. 0 to 14. 0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9. 0 +/- 0. 5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9. 0 to 10. 5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months. RESULTS One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0. 48 mL/s; range, 12 to 55 mL/min [0. 20 to 0. 92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5. 21 +/- 30. 3 g/m2 in the control/delayed treatment group versus 0. 37 +/- 25. 0 g/m2 in the treatment group. Absolute mean difference between groups was 4. 85 g/m2 (95% confidence interval, -4. 0 to 13. 7; P = 0. 28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12. 75 g/dL (127. 5 g/L in treatment group versus 11. 46 g/dL [114. 6 g/L] in control/delayed treatment group; P = 0. 0001). LV growth occurred in 20. 1% in the treatment group versus 31% in the control/delayed treatment group (P = 0. 136). In patients with a stable Hgb level, mean LVMI did not change (-0. 25 +/- 26. 7 g/m2), but it increased in those with decreasing Hgb levels (19. 3 +/- 28. 2 g/m2; P = 0. 002). CONCLUSION This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.
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Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy
Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P, Coyle D, Fine A, Handa P, Kingma I, et al
Kidney International. 2000;58((3):):1325-35.
Abstract
BACKGROUND Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown. METHODS One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation. RESULTS In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004). CONCLUSIONS Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.
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Comparison of subcutaneous and intravenous recombinant human erythropoietin for anemia in hemodialysis patients with significant comorbid disease
Muirhead N, Churchill DN, Goldstein M, Nadler SP, Posen G, Wong C, Slaughter D, Laplante P
American Journal of Nephrology. 1992;12((5):):303-10.
Abstract
While recombinant human erythropoietin (rHuEPO) is an effective therapy for anemia in renal failure, most published studies concern benefits in relatively healthy hemodialysis patients. The present study compares intravenous and subcutaneous administration of rHuEPO in an unselected group of 128 hemodialysis patients who were randomized to receive rHuEPO in an initial dose of 150 U/kg/week in three divided doses by subcutaneous or intravenous injection. Following a 4-week placebo run-in period, patients received rHuEPO until their hemoglobin was stable between 105 and 125 g/l for 4 weeks and then followed for a further 24 weeks. Eighty-three patients completed the study, 45 in the subcutaneous and 38 in the intravenous group. There was no difference in mean hemoglobin at any stage between subcutaneous and intravenous patients. Mean rHuEPO dose at the time of stabilization was significantly lower in the subcutaneous group compared to the intravenous (205.9 +/- 135.4 vs. 274.1 +/- 142.4 U/kg/week; p = 0.019), mean time to hemoglobin target was 9.9 +/- 4.5 weeks for the subcutaneous group and 11.9 +/- 4.9 weeks for the intravenous group (p = 0.037). Time to stabilization was 14.9 +/- 4.7 weeks for the subcutaneous compared to 17.3 +/- 3.9 weeks for the intravenous group (p = 0.006). Diabetic patients had higher dose requirements for rHuEPO at all time points and required a longer time to reach stabilization than nondiabetics (18.6 +/- 4.6 vs. 15.6 +/- 4.3 weeks; p = 0.016). Quality of life estimated by a disease-specific Kidney Disease Questionnaire improved significantly during rHuEPO therapy in both groups. There was no significant change in dialysis prescription throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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Erythropoietin for anaemia in haemodialysis patients: results of a maintenance study (the Canadian Erythropoietin Study Group)
Muirhead N, Laupacis A, Wong C
Nephrology Dialysis Transplantation. 1992;7((8):):811-6.
Abstract
Most published studies of recombinant human erythropoietin (rHuEpo) have been of limited duration and in small patient populations. The present study examines the long-term effects of rHuEpo in 98 haemodialysis patients treated for up to 18 months. All patients had completed a 6 month placebo-controlled study of rHuEpo. Patients previously on placebo (group 1; n = 31) received rHuEpo at an initial dose of 50 U/kg thrice weekly with subsequent dose adjustments to maintain haemoglobin (Hb) in the range 105-120 g/l. Patients previously on rHuEpo (group 2; n = 67) continued on their usual dose with adjustments made to maintain Hb at 105-120 g/l. Haematological parameters were measured every 2 weeks. Quality of life, assessed by a disease-specific kidney disease questionnaire (KDQ), was measured every 6 months. Mean Hb in group 1 increased from 74.2 +/- 11.4 g/l at baseline to 112.9 +/- 12.6 g/l after 12 months of rHuEpo therapy. After 12 weeks of rHuEpo therapy Hb in groups 1 and 2 was indistinguishable. Hb remained constant in both groups throughout the period of follow-up. Mean rHuEpo dose requirements were similar in both groups. At the end of the study the mean intravenous rHuEpo dose in group 1 patients was 176.6 +/- 154.4 and in group 2 patients was 210.0 +/- 144.0 U/kg per week. Access failure was increased during rHuEpo therapy in patients with synthetic grafts (46% versus 7% failures compared to fistulae; P less than 0.001). Group 1 patients receiving rHuEpo had a significant increase in diastolic but not systolic blood pressure despite a 32% increase in overall antihypertensive prescriptions.(ABSTRACT TRUNCATED AT 250 WORDS)