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Thursday, 23 July 2015 23:07

Cochrane Library: Erythropoiesis-stimulating agents for anemia (new evidence summary)

Cochrane Library: Erythropoiesis-stimulating agents for anemia

Introduction

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.

Summary

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 Transplant’s 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.

Questions

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?

Resources

Access other resources

1. Interventions for erythropoietin-resistant anaemia in dialysis patients

2. Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients.

3. Darbepoetin for the anaemia of chronic kidney disease.

4. Haemoglobin and haemocrit targets for the anaemia of chronic kidney disease.

5. Mortality and target haemoglobin concentrations in anaemic pateints with chronic kidney disease treated with erythropoietin: a meta-analysis.

Published in
Anemia, Iron and trace elements

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Cochrane Library: Treatment for Lupus Nephritis

Introduction

Lupus nephritis is an inflammatory condition affecting the kidneys which is caused by systemic lupus erythematosus (SLE), an autoimmune disease that is more common among women. About half of all people with SLE develop lupus nephritis, and of these about 1/10 experience chronic kidney disease or kidney failure. Treatment aims to delay disease progression and achieve remission by stabilising and improving kidney function and minimising side effects. For about the past 30 years, standard treatment for lupus nephritis has focused on a combination of cyclophosphamide (an alkylating agent) and corticosteroids. This Cochrane review assesses the benefits and harms of different immunosuppressive treatments in biopsy-proven proliferative lupus nephritis.

Authors

Lorna Henderson

Lorna Henderson is a Nephrologist based in Edinburgh, and who trained in Scotland and Australia. During a fellowship year at Westmead Hospital in New South Wales, Lorna spent some time training with the Cochrane Renal Group, and working on the review update of treatment for Lupus Nephritis. She has an interest in transplantation and evidence based practice.

Angela Webster

Angela is a Nephrologist and Transplant Physician, having trained in England, Scotland and Australia. She also works at the University of Sydney as a Clinical Epidemiologist and is the Deputy Coordinating Editor of the Cochrane Renal Group

Summary

Lupus nephritis occurs in about half of all people with systemic lupus erythematosus (SLE), leading to end-stage kidney disease (ESKD) in 5% to 10% of patients at 10 years. Studies in the 1970s and 1980s led to the establishment of cyclophosphamide-containing regimens as first line therapy for inducing remission, and survival is now greater than 90%. However, Cyclophosphamide is toxic and associated with high incidence of adverse events. Furthermore, response to treatment is often slow, and although remission is induced in a significant proportion of patients, the risk or relapse or flare remains considerable.

In the past ten years, numerous trials evaluating newer agents (mycophenolate mofetil (MMF), tacrolimus and rituximab) have been published. These have all been proposed as alternative, potentially less toxic, and more effective therapies than cyclophosphamide. This December 2012 update to a Cochrane Review that was last revised in 2004 seeks to evaluate the relative effects of all available immunosuppressive therapies for the induction or maintenance treatment of lupus nephritis.

The principal sources of trials for the review was the Cochrane Renal Group’s Specialized Register, which includes more than 18,000 reports. It is the best single source of published trials for inclusion in systematic reviews in kidney disease, and draws on searches of the Cochrane Central Register of Controlled trials, general bibliographic databases of health research such as MEDLINE and EMBASE, and the checking of specialised databases, journals and conference proceedings.

Two authors independently screened all titles and abstracts to determine which studies to include. Data were extracted and quality assessed independently by two authors, with differences resolved by discussion.

A total of 50 trials involving 2846 randomized participants were included in the review. Most of these were of induction therapy, with six studies (514 participants) comparing different forms of maintenance therapy. Many different comparisons had been investigated in the trials, making it difficult to use this large amount of data to answer specific questions; but two comparisons stood out.

Seven trials, including a total of 710 patients, compared MMF against conventional therapy with intravenous cyclophosphamide for induction treatment. In the short term (up to six months), treatment with MMF conferred similar risk of death and progression to end-stage kidney disease as intravenous cyclophosphamide. Renal remission and renal relapse were equally likely with each agent; but MMF was associated with less ovarian failure, leucopenia and alopecia. However, it seemed to increase the risk of diarrhoea.

Three trials (including a total of 371 patients) compared MMF with azathioprine for maintenance therapy. MMF was associated with a significantly lower risk of renal relapse.

Across the review, there is considerable clinical heterogeneity in interventions, definitions of remission, and outcome reporting. These hampered interpretation and presentation of important outcomes in this review. For example, even in the comparison of MMF versus cyclophosphamide, there was variability among studies in therapeutic dosing, route of administration and co-interventions.

There is also a problem with the duration of follow-up in the trials. Although some studies followed patients for one to two years, others were much shorter and inadequately powered to detect events in the clinically important outcomes. For example, the average time to remission with cyclophosphamide is about 10 months, but 10 of the induction therapy studies did not follow their participants beyond six months. Furthermore, the risk of adverse events such as ovarian failure increases after six months, so the power of existing studies, even when combined, to detect significant differences among interventions is limited. The lack of long-term follow-up is particularly relevant to the outcome of ESKD, where a difference between treatments may not become apparent for several years.

In their conclusions, the authors of this updated review draw attention to the similar effects for induction of remission of proliferative lupus nephritis with MMF compared to cyclophosphamide. They draw attention to the significant reduction in toxic effects (ovarian failure, alopecia and leucopenia) with MMF, but note that the significant increase in diarrhea may limit its widespread tolerability. However, particularly for women of child-bearing age, they suggest that the equivalent remission rates combined with a more favourable side-effect profile would support MMF as being superior to cyclophosphamide as induction therapy for lupus nephritis.

In considering the questions that need to be addressed in future studies, the authors reflect on the fact that many of the treatments that are used for lupus nephritis, including rituximab, tacrolimus and cyclosporin, have only been assesses in small randomized trials, with inconsistent outcome reporting. They highlight two main implications for research: firstly, to make better use of existing data, and secondly to strategically plan any new studies. This recognizes that lupus nephritis is uncommon, and requires multicentre collaboration for any study to have an adequate sample size and prolonged follow-up beyond six months to clarify the harms of specific treatment regimens.

Questions

1. What do you think of the findings of this Cochrane Review?

This review brings together studies testing a variety of induction and maintenance therapies for people with lupus nephritis. Do you prefer this wide-ranging approach or the more focused questions in some Cochrane Reviews which look at a single comparison only?
The authors relied mainly on a search of the specialized register of the Cochrane Renal Group to look for studies for their review, rather than doing their own searches of databases such as MEDLINE and EMBASE. What are the advantages and disadvantages of this approach?

2. How should this review influence decisions about treatments for lupus nephritis?

Few of the intervention comparisons could be brought together in meta-analyses in this review, because of the lack of similar comparisons and the large amount of heterogeneity in the ways that outcomes were measured or reported. If you already knew the results of individual studies that are included in the review, would the review change your confidence about using the results of those studies when making a decision?
If you were responsible for designing a new randomised trial of induction therapy for people with lupus nephritis, how many, and which, drugs would you compare?

3. Would other information help in making a decision about treatments for people with lupus nephritis?

Most of the trials in this review did not follow patients for more than one year, which is too short to detect the effects on some important outcomes. How would you decide on the optimum length of follow-up and, if this proved to be difficult in randomised trials, what other study designs might be used?
If you were a research funder, what things would you consider if you were asked to fund 10 years of follow-up for trials that have already been done or a new trial with 1 year of follow-up?
What evidence would you look for to decide if the results from the trials of induction therapy might help when making decisions about maintenance therapy?

Resources

Access the Cochrane Review

Treatment for lupus nephritis Assessing the benefits and harms of different immunosuppressive treatments in biopsy-proven proliferative lupus nephritis.

Access other resources

1. Dehydroepiandrosterone for systemic lupus erythematosus
Assessing the effectiveness and safety of dehydroepiandrosterone compared to placebo in the treatment of people with systemic lupus erythematosus.

2. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus
Assessing the benefits and harms of cyclophosphamide and methylprednisolone in the treatment of neuropsychiatric manifestations of SLE.

3. Access other reviews from the Cochrane Renal Group

4. Search for reviews from the Renal Group using The Cochrane Library

Published in
Glomerular Disease

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Cochrane Library: Erythropoiesis-stimulating agents for anemia (new evidence summary)

Cochrane Library: Erythropoiesis-stimulating agents for anemia

Introduction

Introduction

Authors

Summary

Summary

Audio Podcast

Audio Podcast

Presentation

Presentation

Questions

Questions

Resources

Resources

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Cochrane Library: Treatment for Lupus Nephritis

Cochrane Library: Treatment for Lupus Nephritis

Introduction

Introduction

Authors

Summary

Summary

Audio Podcast

Audio Podcast

Presentation

Presentation

Questions

Questions

Resources

Resources

Access the Cochrane Review

Access other resources