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

Summary

Background

Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim was to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease.

Methods

We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trial registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks.

Findings

We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1·17, 95% CI 1·01–1·35; p=0·031) and arteriovenous access thrombosis (1·34, 1·16–1·54; p=0·0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1·27, 1·08–1·50; p=0·004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1·31, 0·97–1·78; p=0·075). The incidence of myocardial infarction was much the same in the two groups.

Interpretation

To target higher haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

Introduction

Anaemia is commonly seen in individuals with chronic kidney disease.¹ A reduction in haemoglobin concentrations in these patients has been shown to be associated with impairment in quality of life, reduced energy, neurocognitive decline, decreased exercise capacity, and increased mortality.2, 3, 4, 5 The cause of anaemia in such individuals is mainly related to a deficiency in the synthesis of endogenous erythropoietin.⁶ Therefore, the use of recombinant human erythropoietin represents a logical and commonly used treatment for this disorder. At present, such treatments include erythropoiesis-stimulating agents such as epoetin alfa and beta as well as the analogue of recombinant human erythropoietin, darbepoetin alfa.

Use of recombinant human erythropoietin to treat anaemia caused by chronic kidney disease has been found in some small mechanistic studies to be associated with improvements in muscle strength,⁷ exercise capacity,⁸ fatigue,⁹ neurocognitive function,¹⁰ and depression.¹¹ However, considerable controversy exists with regard to the concentration of haemoglobin at which patients should begin treatment with recombinant human erythropoietin as well as the haemoglobin concentration that should be aimed for to increase benefits to a maximum and to reduce potential adverse effects to a minimum. These adverse effects include the development or worsening of systemic hypertension, site access thrombosis in dialysis patients with arteriovenous shunts, and the apparent potential for increased cardiovascular events.2, 12 The publication of two major studies of recombinant human erythropoietin in chronic kidney disease—Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE)¹³ and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)¹⁴—has raised further the possibility that this treatment might be associated with an increase in cardiovascular events in those individuals in whom a higher haemoglobin concentration is aimed for.

Our aim was to do a meta-analysis of all available data to determine whether targeting different haemoglobin concentrations when treating anaemic patients with chronic kidney disease with erythropoiesis-stimulating agents is associated with altered all-cause mortality and cardiovascular events.