Elsevier

The Lancet

Volume 382, Issue 9900, 12–18 October 2013, Pages 1268-1277
The Lancet

Articles
Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(13)60897-1Get rights and content

Summary

Background

Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease.

Methods

We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model.

Findings

Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61–0·98).

Interpretation

Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder.

Funding

None.

Introduction

Chronic kidney disease is a worldwide public health problem with a yearly incidence as high as 200 cases per million in many countries.1 Cardiovascular disease is the leading cause of death in men and women with chronic kidney disease, and accelerated, progressive vascular calcification might play a part in the development of this disorder.2 The cause of vascular calcification is not known, but probably involves the conversion of vascular smooth muscle cells into bone forming, osteoblast-like, cells. Factors that promote this change in cell type include high concentrations of serum calcium and phosphorus.3 In fact, results of observational studies in patients with chronic kidney disease show an association between cardiovascular mortality and increases in serum calcium, phosphate, and calcium phosphate product.4

Hyperphosphataemia is an important and almost inevitable clinical result of advanced chronic kidney disease, and controlling serum phosphate both by dietary restriction and use of an intestinal phosphate binder (calcium-based or non-calcium-based) is a key focus for clinicians. The possibility that non-calcium-based phosphate binders might—by attenuating positive calcium balance—delay the progression of vascular calcification and cardiovascular and overall mortality needs to be investigated.

Results from individual clinical trials that have examined the relation between calcium-based phosphate binders, vascular calcification, and mortality have been inconclusive—probably because of the small numbers of study participants and outcome events.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 This limitation has left clinicians uncertain as to which type of phosphate binder should be prescribed in patients with chronic kidney disease. To address this uncertainty, in 2009, we did a meta-analysis on the effects of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease.24 On the basis of data from eight randomised controlled trials and 2873 participants, we noted a trend towards a decrease in all-cause mortality in patients taking non-calcium-based phosphate binders versus those taking calcium-based phosphate binders (risk ratio [RR] 0·68, 95% CI 0·41–1·11). We recognised that our findings were limited by low power, and as such could not exclude a potentially important beneficial effect. Thus, we formed a collaborative review group to undertake an updated meta-analysis.

We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. Trials that have been published since our original meta-analysis are inconclusive as to the relation between type of phosphate binder and mortality. As such, we aimed to provide the best available evidence as to which type of phosphate binder clinicians should prescribe to patients with chronic kidney disease.

Section snippets

Search strategy and selection criteria

We did a systematic review in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and meta-Analyses) guidelines.25 The search strategy was developed and undertaken by two experienced medical librarians (TC and MD), who searched for clinical trials published after Aug 1, 2008 (when our previous systematic review ended), up until Oct 22, 2012 (the date of the last search). They searched the electronic databases Ovid Medline (articles published between 1946 and October,

Results

Our updated search identified 847 citations that included our keywords. Of these, 48 were retrieved for more detailed assessment, from which 40 were excluded: 15 because they did not provide information on the outcomes of interest, 18 because they did not present original data (review articles or commentaries), and seven because data was available only in abstract form. As such, we added eight new studies to the ten previously identified and reported studies to our updated meta-analysis (figure

Discussion

Our systematic review of randomised trials included 4622 patients and 936 deaths and showed a 22% reduction in all-cause mortality in patients receiving non-calcium-based phosphate binders (sevelamer or lanthanum) compared with those assigned to calcium-based regimens. We noted similar reductions in mortality in non-randomised trials and when we considered predialysis and dialysis patients separately. Length of follow-up varied in each study; studies with the largest number of patients and

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