Anemia affects nearly all adults with advanced kidney disease and is linked to fatigue, breathlessness, impaired quality of life and physical function, and shorter survival. ESA treatment aims to improve anemia-related symptoms and minimize treatment-related cardiovascular events. Several ESA classes are available for anemia treatment (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta as well as biosimilar ESAs) but whether these drugs have differing benefits and harms is uncertain. This Cochrane review directly compares available ESAs for treatment of anemia among adults with chronic kidney disease.
Authors
Suetonia Palmer
Suetonia is a nephrologist based at the University of Otago, Christchurch in New Zealand, and who trained in New Zealand and the USA. She is an Editor for Cochrane Kidney and Transplant.
Giovanni Strippoli
Giovanni is a nephrologist based at the University of Bari in Italy, who also trained at the Sydney School of Public Health, Australia. He is an Editor for Cochrane Kidney and Transplant and the journal Nephrology, Dialysis and Transplantation.
This Cochrane Kidney and Transplant review from 2014 evaluates which ESA might be safest and most effective for treating the anemia of chronic kidney disease.
It uses the novel technology of network meta analysis which can combine information from all research trials within a single evidence framework to rank ESAs in order of their efficacy and safety.
Anemia affects nearly all adults with advanced kidney disease and is linked to fatigue, breathlessness, impaired quality of life and physical function, and shorter survival. Treating the anemia of chronic kidney disease in the 1970s and 1980s depended on blood transfusions and iron-therapy, which led to blood-borne infections and iron overload. In the 1980s, the erythropoietin gene was cloned leading to the establishment of recombinant erythropoiesis-stimulating agents as standard treatment.
The first developed ESAs were epoetin alfa and epoetin beta, which are given parenterally several times a week. Subsequent drug molecule development has led to additional ESA classes that have an extended duration of action (darbepoetin alfa and methoxy polyethylene glycol-epoetin beta). As proprietary ESA drugs come off patent, biosimilar preparations of epoetin alfa and epoetin beta are increasingly available.
Since their development, the evidence for ESAs has largely assessed whether treatment targeting a higher hemoglobin value is more effective and safer than a lower hemoglobin value. In the last 20 years it has become evident that ESA treatment targeting a higher hemoglobin level increases mortality and death. This has resulted in greater balancing of the benefits of ESA treatment against potential toxicity in clinical practice. However, evidence about whether the several available ESAs have differing benefits and harms has not been previously summarized.
The central source of trials in this review was the Cochrane Kidney and Transplants specialized register which houses more than 18 000 research reports. The register is the best curated source of trials in kidney disease which is drawn from citations in the Cochrane library, checking of journals and conference proceedings by hand, and automated searches of electronic bibliographies including MEDLINE and EMBASE.
During this review process, two authors assessed all potential trials that addressed the clinical question. Information about the trial methodology and clinical endpoints was extracted by two independent authors. The quality of the contributing trials was also evaluated.
A total of 56 trials among 15,596 randomized participants were included in the review. Most studies involved dialysis patients. Treatment was generally short-term (6 months) and most studies compared one ESA against another (a minority compared treatment to placebo).
All ESA treatments appeared to have similar risks of death and cardiovascular mortality. All ESAs prevented the need for blood transfusions, although there was less information for biosimilar ESAs. ESAs all incurred hypertension while there were no discernible differences between ESAs for risks of subsequent major cardiovascular events. There was not enough information to assess whether different ESAs had different effects on patient fatigue or breathlessness, or protected against kidney failure.
Across the studies, many drug evaluations were of short duration or not specifically designed to assess patient outcomes such as survival or cardiovascular disease, lowering our confidence in the results. The lack of longer term follow up beyond six months meant that the studies lacked power to provide precise answers to questions about treatment impact on patient survival and risks of heart and vascular disease, even when combined in a single framework. There was also important clinical diversity in participant clinical characteristics, treatment doses, and the severity of kidney disease although the consequences of this variability on the review findings could not be explored.
The review authors conclude that there is currently no strong evidence that ESAs have different benefits (preventing blood transfusions) or toxicity effects (vascular events or mortality) compared to each other or placebo. They draw attention to the sparse information about some key patient-centered outcomes of treatment such as fatigue and breathlessness.
In considering the questions that need to be addressed in future studies, the authors reflect on the relative lack of information for biosimilar ESAs in treatment of anemia. In addition, given there is little evidence that clinical effects of ESAs are different, drug costs and availability, and patient preferences about dosing frequency might be considered as a basis for individualizing anemia care among people with chronic kidney disease. This recognizes that future large studies comparing different ESAs are unlikely.
1. What do you think of the findings of this Cochrane Review?
This review brings together different treatments within a network analysis, including comparing treatments when head-to-head trials comparing drugs are not available. Do you consider this approach appropriate or do you prefer direct drug comparisons as evaluated in standard Cochrane reviews and randomized trials even though this results in a lack of evidence for some drug treatments?
Do you think there were other treatment endpoints that should be considered when making decisions about the benefits and harms of anemia treatment in people with kidney disease (including hemoglobin targets)?
2. How should this review influence decisions about treatments for anemia of chronic kidney disease?
Few of the trials of erythropoiesis-stimulating agents have measured patient-reported symptoms of anemia including tiredness and breathlessness. Would better understanding about whether treatment impacts on these symptoms change the way you prescribe these medications?
The analysis only included erythropoiesis-stimulating agents (as opposed to a broader review that might have included iron supplementation)? Would a broader review scope change your practice to a greater extent than the current approach?
3. Would other information would help in making decisions about treatments for people with anemia and chronic kidney disease?
The included studies were 6 months in duration on average? Would you consider this too short to detect the effects of treatment on important outcomes such as mortality? How would you decide on the optimum length of follow up and which treatment endpoints would be important for your practice?
The review suggests similar effects of differing ESAs for a range of outcomes, but information about biosimilar preparations was less available. Would you have confidence in the findings of this review when considering biosimilar ESA therapy?
This review did not provide information about ESA treatment in children. What evidence would you look for to decide about treatments in the pediatric population?
