American Journal of Kidney Diseases
Volume 55, Issue 3 , Pages 423-425, March 2010

Quality of Life in CKD Patients Treated With Erythropoiesis-Stimulating Agents

  • Patrick S. Parfrey, MD, FRCPC

      Affiliations

    • Corresponding Author InformationAddress correspondence to Patrick S. Parfrey, MD, FRCPC, Clinical Epidemiology Unit, Health Sciences Centre, Memorial University, St. John's, Newfoundland, Canada A1B 3V6
    • ,
  • Tyler Wish, BSc

Memorial University, St. John's, Newfoundland

Article Outline

 

Related Articles, pp. 519 and 535

Anemia occurs frequently in patients with chronic kidney disease (CKD), and if untreated, hemoglobin (Hb) levels may decrease to < 8 g/dL in patients with end-stage renal disease.1 Symptoms attributed to anemia include low energy, fatigue, decreased physical function, and low exercise capacity.2 Erythropoiesis-stimulating agents (ESAs) originally were accepted into clinical nephrology practice because they increased hemoglobin levels, decreased blood transfusions, and improved quality of life.1, 3 However, after their introduction, considerable controversy ensued concerning the optimal target Hb level and the potential of ESAs to be harmful at target Hb levels > 12 g/dL.4, 5, 6, 7, 8 Furthermore, it is unclear whether these target Hb levels result in clinically meaningful improvements in quality of life. Two articles by Gandra et al9 and Johansen et al10 published in this issue of the American Journal of Kidney Diseases are valuable reviews of data concerning quality-of-life domains likely to respond to ESA therapy.

Dialysis patients have a short life expectancy, similar to that associated with some common cancers,11 and improving quality of life may be more important than prolonging survival. Also, healthier patients with CKD and anemia want and/or need to work, an objective that may be limited by symptoms attributable to anemia. The recent mandate by the Centers for Medicare & Medicaid Services in the United States that all dialysis units monitor health-related quality of life emphasizes its importance.12

The decision to prescribe ESAs requires patients and their physicians to balance benefits that include improvement in some domains of life quality and decrease in blood transfusions against risks that include loss of vascular access4 and neurologic events.5, 8 Recently, a large placebo-controlled, double-blind, randomized controlled clinical trial (Trial to Reduce Cardiovascular Events With Aranesp Therapy [TREAT]) in diabetic patients with nondialysis CKD and moderate anemia (baseline Hb level, 10.4 g/dL) showed that darbepoetin alfa treatment was associated with increased risk of stroke, modest improvement in patient-reported fatigue, and fewer blood transfusions.8 For target Hb levels > 12 g/dL, there is no evidence to suggest that ESA use improves cardiovascular or renal outcomes,4, 5, 6, 7, 8 and whether this target results in clinically meaningful improvements in quality of life sufficient to offset the risks is questionable.

Investigation of ESAs and quality of life is complicated by: (1) classification of patients, (2) research design, (3) choice of instruments used to measure quality of life, and (4) definition of clinically meaningful improvement in quality-of-life domains.

1.Patients with kidney failure treated using dialysis are “captive,” followed up frequently, and likely to get severe anemia if untreated, whereas patients with earlier stages of CKD receive treatment in the community, are followed up infrequently, and are likely to develop moderate anemia unless close to dialysis therapy initiation. Therefore, it is important to examine the efficacy of treating severe anemia (eg, Hb < 10 g/dL) separately from the efficacy of treating moderate anemia (eg, Hb > 10 g/dL).

2.Quality of life is evaluated best in double-blind randomized controlled trials (RCTs). Because quality of life is subjective, both the patient and recorder should be blind to the therapy being evaluated. However, most available data have arisen from open-label studies. Furthermore, it is critical to have matched control groups to test an intervention, because all patients who enter a prospective study may perceive benefit that is unrelated to the intervention.

3.Multiple instruments are available to measure quality of life, and they often have multiple domains. It seems reasonable to decide a priori which domains are relevant to anemia therapy; for example, energy/fatigue, physical function, and exercise tolerance. Some instruments have been validated in patients with CKD (eg, Kidney Disease Quality of Life [KDQOL]), whereas others have not (Functional Assessment of Cancer Therapy Fatigue [FACT]). However, the latter has been validated in patients with similar levels of quality of life: oncology patients.

4.Clinically meaningful improvement in quality-of-life scores may be examined by effect size: differences in mean scores divided by the standard deviation of the first mean.9 However, it probably is of interest to know the proportion of patients who had a clinically-meaningful improvement in the relevant score compared with that in a control group. Some definitions for quality-of-life outcomes are provided in the report by Gandra et al.9

In this issue of AJKD, the systematic review by Gandra et al9 examines the impact of ESAs on energy and physical function in nondialysis patients with CKD, and the report by Johansen et al10 provides a systematic review of physical function and meta-analysis of exercise tolerance in dialysis patients treated with ESAs.

The 14 reports reviewed by Gandra et al9 show the methodologic problems in evaluating the impact of ESAs. These studies show considerable between-study heterogeneity in terms of patient characteristics, starting Hb concentrations (range, 8.0-11.9 g/dL), target Hb concentrations, durations of follow up (8-96 weeks), choice of quality-of-life instrument, and research design. One limitation of this review is that because there are few randomized placebo-controlled trials of the subject, it relies heavily on open-label RCTs and single-arm studies, which are inherently more susceptible to bias.

Only 1 placebo-controlled RCT of reasonable size (N = 110), the US Recombinant Human Erythropoietin Predialysis Study Group, of nondialysis patients with CKD was available for review.13 A significant improvement in energy in patients randomly assigned to ESA therapy compared with placebo was reported. However, the clinical relevance of the finding could not be determined because an unspecified instrument was used to collect patient-reported energy.13 The other RCTs (N = 6) were open label.

Using the 36-Item Short-Form Health Survey (SF-36) Vitality subscore as an outcome, the RCT by Revicki et al14 (N = 35) showed a statistically and clinically significant effect of partial correction of anemia compared with placebo in patients who had severe anemia at baseline. The Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) Study showed a statistically significant effect of early correction of moderate anemia compared with later treatment, the impact of which likely was of moderate clinical significance,7 whereas the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) Study showed clinical improvement in both the group allocated to full correction and the group allocated to partial correction of anemia.6 Similar results were obtained for the SF-36 Physical Function subscale.6, 7, 14 In TREAT, a double-blind placebo-controlled RCT of 4,038 patients with diabetes with moderate anemia, the only domain of quality of life reported in the primary report was fatigue, measured using the FACT instrument.8 In the group allocated to full correction of anemia, statistically better scores of marginal clinical significance were observed compared with the control group. Results using the SF-36 currently are being analyzed.

In the review by Johansen et al,10 28 studies of dialysis patients evaluated exercise tolerance, but only 3 were RCTs. The Canadian Erythropoietin Study Group evaluated the treatment of severe anemia and found a significant increase in 6-minute walking in the combined epoetin alfa groups compared with placebo, but no significant difference between the high- and low-Hb-target groups.1 The double-blind Canadian-European RCT in 596 “healthy” patients also found no difference between the high- and low-Hb-target groups.5 Similar results were observed for KDQ physical function scores in these 2 studies.1, 15 However, in the Canadian-European RCT, statistically significant improvements of moderate clinical significance were observed in the high-Hb groups for the SF-36 Vitality subscore and KDQOL fatigue scores compared with the low-Hb group.5, 15

In nondialysis patients with CKD and dialysis patients, the evidence to support treatment of moderate anemia (Hb, 10-12 g/dL) with ESA therapy is tenuous. Both reviews published in this issue of AJKD suggest that improvements in quality of life are maximized in the 10-12–g/dL range.9, 10 The improvement in some quality-of-life domains at a higher Hb target is of moderate clinical significance when observed.5, 7, 15 In TREAT, a clinically meaningful improvement in fatigue scores occurred in 55% of patients assigned to darbepoetin alfa therapy compared with 50% in the placebo group (P = 0.002).8 Although there also is a decrease in blood transfusions at the high-Hb target,8, 16 these benefits are offset by the risk of major side effects. In patients with diabetes, the risk of stroke attributable to ESAs reported by TREAT was ∼1% per year.8 In dialysis patients, risk of stroke also has been reported,5 and there is substantial risk of vascular access clotting and loss.4

Evidence to support treatment of severe anemia is stronger because the quality-of-life benefits are greater and high transfusion requirements are substantially decreased.1, 3 Results from TREAT suggest that the Hb level at which ESAs should be prescribed requires assessment of risks and benefits for individual patients. However, the safety of ESAs in treating severe anemia has not been evaluated in large placebo-controlled randomized trials. In the absence of such data, current guidelines that recommend a target Hb level of 10-12 g/dL for ESA therapy seem reasonable.

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Acknowledgements 

Mr Wish is a PhD student in Clinical Epidemiology.

Financial Disclosure: Dr Parfrey has received research funding from Amgen and Ortho Biotech for randomized trials of ESA therapy. Mr Wish declares that he has no relevant financial interests.

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References 

  1. Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis. BMJ. 1990;200:573–578
  2. Delano BG. Improvements in quality of life following treatment with r-HuEPO in anemic hemodialysis patients. Am J Kidney Dis. 1989;14:14–18
  3. Evans RW, Rader B, Manninen DL. The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. JAMA. 1990;263:825–830
  4. Besarab A, Bolton WK, Browne JK, et al. 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. 1998;339:584–590
  5. Parfrey P, Foley R, Wittreich B, Sullivan D, Zagari M, Frei D Canadian European Study Group. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005;16:2180–2189
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  9. Gandra SR, Finkelstein FO, Bennett AV, Lewis EF, Bragg T, Martin ML. Impact of erythropoiesis-stimulating agents on energy and physical function in nondialysis CKD patients with anemia: a systematic review. Am J Kidney Dis. 2010;55(3):519–534
  10. Johansen KL, Finkelstein FO, Revicki DA, Gitlin M, Evans C, Mayne TJ. Systematic review and meta-analysis of exercise tolerance and physical functioning in dialysis patients treated with erythropoiesis-stimulating agents. Am J Kidney Dis. 2010;55(3):535–548
  11. US Renal Data System. Morbidity and mortality. USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2008;chapt 6
  12. Finkelstein FO, Wuerth D, Finkelstein SH. Health related quality of life and the CKD patient: challenges for the nephrology community. Kidney Int. 2009;76:946–952
  13. The US Recombinant Human Erythropoietin Predialysis Study Group. Double-blind, placebo-controlled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients. Am J Kidney Dis. 1991;18:49–50
  14. Revicki DA, Brown RE, Feeny DH, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995;25:548–554
  15. Foley RN, Curtis BM, Parfrey PS. Erythropoietin therapy, hemoglobin targets, and quality of life in healthy hemodialysis patients: a randomized trial. Clin J Am Soc Nephrol. 2009;4:726–733
  16. Foley RN, Curtis BM, Parfrey PS. Hemoglobin targets and blood transfusions in hemodialysis patients without symptomatic cardiac disease receiving erythropoietin therapy. Clin J Am Soc Nephrol. 2008;3:1669–1675

PII: S0272-6386(09)01589-3

doi:10.1053/j.ajkd.2009.12.014

Refers to article:

  • Impact of Erythropoiesis-Stimulating Agents on Energy and Physical Function in Nondialysis CKD Patients With Anemia: A Systematic Review , 23 December 2009

    Shravanthi R. Gandra, Fredric O. Finkelstein, Antonia V. Bennett, Eldrin F. Lewis, Tracy Brazg, Mona L. Martin
    American Journal of Kidney Diseases March 2010 (Vol. 55, Issue 3, Pages 519-534)

  • Systematic Review and Meta-analysis of Exercise Tolerance and Physical Functioning in Dialysis Patients Treated With Erythropoiesis-Stimulating Agents , 04 February 2010

    Kirsten L. Johansen, Fredric O. Finkelstein, Dennis A. Revicki, Matthew Gitlin, Christopher Evans, Tracy J. Mayne
    American Journal of Kidney Diseases March 2010 (Vol. 55, Issue 3, Pages 535-548)

American Journal of Kidney Diseases
Volume 55, Issue 3 , Pages 423-425, March 2010

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