NIHR Signal Uncertainty persists over choice of phosphate binders for chronic kidney disease

Published on 30 August 2016

NICE recommend calcium-based phosphate binding medicines for people with chronic kidney disease, however, new research suggests non-calcium based alternatives might lead to a lower risk of death.

The review is best viewed alongside other reviews which look at different aspects of chronic kidney disease. The totality of research and cost effectiveness will need to be considered if practice recommendations are to change.

In this review, calcium-based phosphate binders were associated with increased risk of death compared with non-calcium alternatives, but there was no difference in the risk of cardiovascular death or hospitalisation. Effects of these agents on mortality need to be weighed up along with their effects on bone and heart disease. The extent of any reduction in mortality associated with use of phosphate binders compared to placebo is also assessed in another review (Palmer et al).

NICE guidance from 2013 on this topic is due for review in 2017.

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Why was this study needed?

About one in five men and one in four women aged 65 to 74 have some degree of chronic kidney disease, a long-term condition where the kidneys are not able to filter waste products from the blood effectively.

As kidneys begin to lose their function phosphate levels in the blood may increase. The phosphate binds to calcium which is slowly lost from bone, which increases fracture risk, and deposits in the blood vessels, which raises the risk of heart attacks.

Phosphate levels may be lowered by reducing intake in the diet or by using agents to bind phosphate in the gut and reduce its absorption.

Many phosphate binding medicines are available but it is not clear which works best.

This review gathered relevant trial evidence that compared impact of treatments on death rates from all causes, death rates from heart disease or hospital admission due to any cause.

What did this study do?

This systematic review searched for published trials comparing phosphate binders with a control group of phosphorus-restricted diet, placebo or no intervention. It found 28 moderate-to-low-quality trials lasting a minimum of four weeks including 8,335 adults.

Phosphate binders fell into two groups: calcium-based phosphate binders (calcium acetate, calcium citrate or calcium carbonate), and non-calcium-based phosphate binders (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate).

The researchers pooled results from head-to-head trials in standard meta-analysis and also made indirect comparisons across trials using network meta-analysis. This latter type of meta-analysis is informative, but generally less precise than when treatments are directly compared.

The analysis grouped together individual medicines, for example all calcium-based options, which may mask important differences between them. For instance the approach might disguise differences between calcium acetate and calcium carbonate.

What did it find?

  • Risk of death from any cause was higher with calcium-based phosphate binders compared with sevelamer (relative risk [RR] 1.89, 95% confidence interval [CI] 1.02 to 3.50, moderate quality evidence, network meta-analysis), and compared with all non-calcium-based phosphate binders as a group (RR 1.76, 95% CI 1.21 to 2.56, moderate quality evidence, standard meta-analysis).
  • There was no difference in cardiovascular deaths between calcium and non-calcium-based phosphate binders (RR 2.54, 95% CI, 0.67 to 9.62, low quality evidence, standard meta-analysis).
  • There was no difference in hospitalisations between calcium and non-calcium-based phosphate binders (RR 1.28, 95% CI, 0.94 to 1.74, moderate quality evidence, standard meta-analysis).

What does current guidance say on this issue?

NICE guidance from 2013 on management of high phosphate levels in adults with advanced chronic kidney disease (stage 4 or 5) recommends calcium acetate as the medication of choice to control phosphate levels, alongside dietary management.

If calcium acetate is not tolerated or patients find it unpalatable, calcium carbonate is recommended second-line. Switching to a non-calcium-based binder is recommended if calcium drugs are not tolerated, blood calcium gets too high or parathyroid levels get too low.

What are the implications?

This review suggests calcium-based phosphate binders might raise the risk of death from all causes compared to non-calcium-based phosphate binders. This needs to be considered alongside their beneficial effects on bone and blood vessels.

Recommendations by NICE consider cost effectiveness, which is not assessed in this review: non-calcium phosphate binders are currently much more expensive but this may change when these agents lose their patent protection. If the quality of the underlying evidence has improved, this and the reviews (Palmer et al and Jamal et al) may inform the next update of NICE guidance which is due by June 2017.

Citation and Funding

Sekercioglu N, Thabane L, Díaz Martínez JP, et al. Comparative effectiveness of phosphate binders in patients with chronic kidney disease: a systematic review and network meta-analysis. PLoS One. 2016;11(6):e0156891.

This review reported no specific funding for the work.

Bibliography

NHS Choices. Chronic kidney disease. London: Department of Health; 2015.

NICE. Chronic kidney disease (stage 4 or 5): management of hyperphosphataemia. CG157. London: National Institute for Health and Care Excellence; 2013 (see also Tools and resources).

NICE. Hyperphosphataemia in chronic kidney disease. Clinical case scenarios for adult renal services. CG157. London: National Institute for Health and Care Excellence; 2013.

NICE. Management of hyperphosphataemia. Costing report. CG157. London: National Institute for Health and Care Excellence; 2013.

Jamal SA, Vandermeer B, Raggi P, et al. 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. The Lancet. 2013;382(9900):1268-77.

Palmer S, Gardner S, Tonelli M, et al. Phosphate-binding agents in adults with CKD: a network meta-analysis of randomized trials. Am J of Kidney Dis. 2016. [Epub ahead of print].

Why was this study needed?

About one in five men and one in four women aged 65 to 74 have some degree of chronic kidney disease, a long-term condition where the kidneys are not able to filter waste products from the blood effectively.

As kidneys begin to lose their function phosphate levels in the blood may increase. The phosphate binds to calcium which is slowly lost from bone, which increases fracture risk, and deposits in the blood vessels, which raises the risk of heart attacks.

Phosphate levels may be lowered by reducing intake in the diet or by using agents to bind phosphate in the gut and reduce its absorption.

Many phosphate binding medicines are available but it is not clear which works best.

This review gathered relevant trial evidence that compared impact of treatments on death rates from all causes, death rates from heart disease or hospital admission due to any cause.

What did this study do?

This systematic review searched for published trials comparing phosphate binders with a control group of phosphorus-restricted diet, placebo or no intervention. It found 28 moderate-to-low-quality trials lasting a minimum of four weeks including 8,335 adults.

Phosphate binders fell into two groups: calcium-based phosphate binders (calcium acetate, calcium citrate or calcium carbonate), and non-calcium-based phosphate binders (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate).

The researchers pooled results from head-to-head trials in standard meta-analysis and also made indirect comparisons across trials using network meta-analysis. This latter type of meta-analysis is informative, but generally less precise than when treatments are directly compared.

The analysis grouped together individual medicines, for example all calcium-based options, which may mask important differences between them. For instance the approach might disguise differences between calcium acetate and calcium carbonate.

What did it find?

  • Risk of death from any cause was higher with calcium-based phosphate binders compared with sevelamer (relative risk [RR] 1.89, 95% confidence interval [CI] 1.02 to 3.50, moderate quality evidence, network meta-analysis), and compared with all non-calcium-based phosphate binders as a group (RR 1.76, 95% CI 1.21 to 2.56, moderate quality evidence, standard meta-analysis).
  • There was no difference in cardiovascular deaths between calcium and non-calcium-based phosphate binders (RR 2.54, 95% CI, 0.67 to 9.62, low quality evidence, standard meta-analysis).
  • There was no difference in hospitalisations between calcium and non-calcium-based phosphate binders (RR 1.28, 95% CI, 0.94 to 1.74, moderate quality evidence, standard meta-analysis).

What does current guidance say on this issue?

NICE guidance from 2013 on management of high phosphate levels in adults with advanced chronic kidney disease (stage 4 or 5) recommends calcium acetate as the medication of choice to control phosphate levels, alongside dietary management.

If calcium acetate is not tolerated or patients find it unpalatable, calcium carbonate is recommended second-line. Switching to a non-calcium-based binder is recommended if calcium drugs are not tolerated, blood calcium gets too high or parathyroid levels get too low.

What are the implications?

This review suggests calcium-based phosphate binders might raise the risk of death from all causes compared to non-calcium-based phosphate binders. This needs to be considered alongside their beneficial effects on bone and blood vessels.

Recommendations by NICE consider cost effectiveness, which is not assessed in this review: non-calcium phosphate binders are currently much more expensive but this may change when these agents lose their patent protection. If the quality of the underlying evidence has improved, this and the reviews (Palmer et al and Jamal et al) may inform the next update of NICE guidance which is due by June 2017.

Citation and Funding

Sekercioglu N, Thabane L, Díaz Martínez JP, et al. Comparative effectiveness of phosphate binders in patients with chronic kidney disease: a systematic review and network meta-analysis. PLoS One. 2016;11(6):e0156891.

This review reported no specific funding for the work.

Bibliography

NHS Choices. Chronic kidney disease. London: Department of Health; 2015.

NICE. Chronic kidney disease (stage 4 or 5): management of hyperphosphataemia. CG157. London: National Institute for Health and Care Excellence; 2013 (see also Tools and resources).

NICE. Hyperphosphataemia in chronic kidney disease. Clinical case scenarios for adult renal services. CG157. London: National Institute for Health and Care Excellence; 2013.

NICE. Management of hyperphosphataemia. Costing report. CG157. London: National Institute for Health and Care Excellence; 2013.

Jamal SA, Vandermeer B, Raggi P, et al. 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. The Lancet. 2013;382(9900):1268-77.

Palmer S, Gardner S, Tonelli M, et al. Phosphate-binding agents in adults with CKD: a network meta-analysis of randomized trials. Am J of Kidney Dis. 2016. [Epub ahead of print].

Comparative Effectiveness of Phosphate Binders in Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis

Published on 9 June 2016

Sekercioglu, N.,Thabane, L.,Diaz Martinez, J. P.,Nesrallah, G.,Longo, C. J.,Busse, J. W.,Akhtar-Danesh, N.,Agarwal, A.,Al-Khalifah, R.,Iorio, A.,Guyatt, G. H.

PLoS One Volume 11 , 2016

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been linked to poor health outcomes, including diminished quality and length of life. This condition is characterized by high phosphate levels and requires phosphate-lowering agents-phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on patient-important outcomes in patients with CKD-MBD. METHODS: Data sources included MEDLINE and EMBASE Trials from 1996 to February 2016. We also searched the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD, randomized them to receive calcium (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet, placebo or no treatment, and reported effects on all-cause mortality, cardiovascular mortality or hospitalization at >/=4 weeks follow-up. We performed network meta-analyses (NMA) for all cause-mortality for individual agents (seven-node analysis) and conventional meta-analysis of calcium vs. NCBPBs for all-cause mortality, cardiovascular mortality and hospitalization. In the NMAs, we calculated the effect estimates for direct, indirect and network meta-analysis estimates; for both NMA and conventional meta-analysis, we pooled treatment effects as risk ratios (RR) and calculated 95% confidence intervals (CIs) using random effect models. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each paired comparison. RESULTS: Our search yielded 1190 citations, of which 71 RCTs were retrieved for full review and 15 proved eligible. With 13 eligible studies from a prior review, we included 28 studies with 8335 participants; 25 trials provided data for our quantitative synthesis. Results suggest higher mortality with calcium than either sevelamer (NMA RR, 1.89 [95% CI, 1.02 to 3.50], moderate quality evidence) or NCBPBs (conventional meta-analysis RR, 1.76 [95% CI, 1.21 to 2.56, moderate quality evidence). Conventional meta-analysis suggested no difference in cardiovascular mortality between calcium and NCBPBs (RR, 2.54 [95% CI, 0.67 to 9.62 low quality evidence). Our results suggest higher hospitalization, although non-significant, with calcium than NCBPBs (RR, 1.293 [95% CI, 0.94 to 1.74, moderate quality evidence). DISCUSSION/CONCLUSIONS: Use of calcium results in higher mortality than either sevelamer in particular and NCBPBs in general (moderate quality evidence). Our results raise questions about whether administration of calcium as an intervention for CKD- MBD remains ethical. Further research is needed to explore the effects of different types of phosphate binders, including novel agents such as iron, on quality and quantity of life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD-42016032945.

What is network meta-analysis?

Meta-analysis means pooling the results of multiple trials together. In a standard meta-analysis all pooled trials have directly compared the same treatments. A network meta-analysis involves indirect comparisons. For example, if drug A works better than a placebo in one trial, and drug B works better than a placebo in a second trial, a network analysis enables you estimate whether drug A works better than drug B based on the common comparator – the placebo.

This comparison is called indirect because drug A and B have not been compared directly in the same trial.

Expert commentary

The systematic review demonstrates significantly higher all-cause mortality associated with the use of calcium-based compared with non-calcium-based phosphate binders, specifically when compared with sevelamer. Curiously, another recent meta-analysis by Palmer et al shows that none of the phosphate binders, either calcium or non-calcium based, reduces mortality when compared with placebo, but lower mortality with sevelamer compared with calcium-based binders.

There is need for trials of sufficient power and duration to answer whether phosphate binders reduce mortality and if they do, whether there is a difference between different types of binders in this respect.

Dr Indranil Dasgupta, Consultant Nephrologist, Heart of England NHS Foundation Trust

Categories

  •   Medicines, Musculo-skeletal disorders, Renal and urogenital disorders