ESAs Do Not Improve HRQoL in Patients With Anemia and CKD

Nicola M. Parry, DVM

February 17, 2016

In patients with chronic kidney disease (CKD) who have anemia, treating with erythropoietin-stimulating agents (ESAs) to obtain higher hemoglobin targets does not appear to improve health-related quality of life (HRQoL), even for younger, healthier patients, a new study has suggested.

David Collister MD, from the University of Manitoba, Winnipeg, Canada, and colleagues published the results of their systematic review and meta-analysis online February 15 in the Annals of Internal Medicine.

"ESA treatment of anemia in patients with dialysis-dependent and -independent CKD to higher hemoglobin targets did not result in statistically or clinically significant differences in HRQoL," the authors write.

For patients with anemia of CKD, ESAs are a cornerstone of treatment and are used to increase hemoglobin levels. These agents reduce the need for blood transfusions; however, the optimum target hemoglobin levels for these patients is controversial. Many clinicians also believe that treatment of anemia is associated with improvements in HRQoL in patients with CKD, and therefore individualize ESA therapy.

However, according to the authors, prior systematic reviews have limited their focus to dialysis recipients or have included only specific HRQoL domains. These studies also did not include findings from recent large randomized controlled trials (RCTs).

Dr Collister and colleagues therefore aimed to provide an updated synthesis of the evidence from all available RCTs that investigated the use of ESAs to improve HRQoL in patients with CKD who have anemia. In performing this systematic review and meta-analysis, the researchers searched various electronic databases to identify studies for inclusion. They included only prospective RCTs that were reported in English.

Among the 17 included studies involving 10,049 patients with CKD who were receiving ESA treatment for anemia, studies consisted of patients not undergoing dialysis (n = 12), those undergoing dialysis (n = 4), and a mixture of both (n = 1). Thirteen of these studies reported 36-Item Short Form Survey (SF-36) outcomes, and four reported Kidney Disease Questionnaire outcomes, both of which are validated instruments that measure patient-reported HRQoL.

Of the total number of patients involved in these studies, 7616 were predialysis patients, 2387 were hemodialysis recipients, and 46 were peritoneal dialysis recipients.

Pooled analyses of the data from these studies showed that compared with lower hemoglobin target levels, higher targets resulted in no statistically or clinically significant improvement in SF-36 or Kidney Disease Questionnaire HRQoL domains.

Furthermore, in various subgroup analyses, including one that involved only those studies at low risk for bias, differences were still not statistically significant. However, the authors noted that a subgroup analysis of patients with nondialysis CKD showed that this subpopulation may derive more benefit from higher hemoglobin targets than those receiving dialysis, possibly because of the relative preservation of renal function in nondialysis patients. But they stressed that ESAs should still be used with caution in this subpopulation because they remain at high risk for cardiovascular events.

Although the authors acknowledge the statistical and clinical heterogeneity among studies, the lack of good-quality studies, and possible publication bias as limitations of this study, they emphasize that their findings are consistent with those of previous smaller studies and rule out meaningful benefit of ESAs on HRQoL in this patient population.

"Current guidelines for lower hemoglobin targets in patients with CKD requiring treatment for anemia are appropriate to avoid increases in morbidity and mortality while preserving HRQOL and limiting health care costs," they write. "Our findings do not support individualization of hemoglobin targets even in younger patients. Further research into non-ESA agents that increase hemoglobin and their effects on morbidity, mortality, and HRQOL are needed," the authors conclude.

HRQoL is an important measure for studies to assess when considering therapeutics, Jeffrey S. Berns, MD, professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia, told Medscape Medical News. "What's important to the patient is their quality of life. If we raise their hemoglobin levels with an ESA, but it doesn't confer any discernible benefit to the patient, then what have we accomplished?" he said. Indeed, the US Food and Drug Administration encourages the use of patient-centered outcomes measures in clinical trials, he added.

However, he emphasized that this particular study addresses patients with CKD who have relatively mild anemia. As a consequence, when considering groups of patients in this population, "it is unrealistic to expect that raising hemoglobin levels from 10 to 12 g/dL will have a major impact on average HRQoL and physical function measures," he said.

"Even in the absence of a HRQoL reason to use these medications, there is still good reason to use ESAs in some patients," Dr Berns said. Their sole indication is transfusion avoidance, which still remains an important clinical benefit for all patients with CKD, especially those who want a kidney transplant, because transfusions increase the risk for immunological sensitization, he noted.

But improvement in HRQoL would still certainly be a desired benefit of using ESAs, particularly in patients with more severe clinical anemia, Dr Berns added. Some patients feel better and have more energy when they have somewhat higher hemoglobin levels, and are therefore better able to work, exercise, and participate in sports, he explained. Therefore, "at least in some individuals, there may be the opportunity to improve HRQoL, particularly if one can avoid severe anemia. And in others who lead more active lifestyles, even moderate anemia may impair their quality of life," he said.

Dr Berns also raised the question of how best to treat patients with CKD with anemia whose demographics differ from those of the patients in this particular study. Most patients in the large RCTs were typically in the 60- to 65-year age range, with significant comorbidities such as diabetes, heart disease, or peripheral vascular disease. Conversely, many clinicians struggle to treat younger patients with anemia of CKD who are otherwise healthy and without any comorbidities and who have a hemoglobin level of 9 or 10 g/dL, he noted. Although Dr Berns' practice is to try to raise their hemoglobin levels higher than this, he stressed that this particular patient population has not been studied: "Painting all of our CKD patients with the same brush may do a disservice to a population who would have an important quality of life benefit, potentially, although it hasn't been proven."

As is the case with all clinical studies, "as clinicians, it is important that we assess the generalizability of this [study] and apply it to an appropriate patient population, but not every patient population," Dr Berns concluded.

This study was supported by funding from KRESCENT and Manitoba Health Research Council Establishment. One coauthor serves on the scientific advisory board at NxStage outside the study, and another coauthor serves on the medical advisory board at Takeda and Otsuka outside the study. The other study authors and Dr Berns have disclosed no relevant financial relationships.

Ann Intern Med. Published online February 16, 2016. Abstract

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