Effects of different phosphate lowering strategies in patients with CKD on laboratory outcomes: A systematic review and NMA

Abstract

Background: Chronic kidney disease-mineral and bone disorder (CKD-MBD), a complication of chronic kidney disease, has been linked to reduced quality and length of life. High serum phosphate levels that result from CKD-MBD require phosphate-lowering agents, also known as phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on laboratory outcomes in patients with CKD-MBD.

Methods: Data sources included MEDLINE and EMBASE from January 1996 to April 2016, and 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 and randomized them to receive calcium-based phosphate binders (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 (diet), placebo or no treatment and reported effects on serum levels of phosphate, calcium and parathyroid hormone. We performed Bayesian network meta-analyses (NMA) to calculate the effect estimates (mean differences) and 95% credible intervals for serum levels of phosphate, calcium and parathyroid hormone. We calculated direct, indirect and network meta-analysis estimates using random-effects models. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each pairwise comparison.

Results: Our search yielded 1108 citations; 71 RCTs were retrieved for full review and 16 proved eligible. Including an additional 13 studies from a previous review, 29 studies that enrolled 8335 participants proved eligible; 26 trials provided data for quantitative synthesis. Sevelamer, lanthanum, calcium, iron, diet and combinations of active treatments (calcium or sevelamer or lanthanum and combination of calcium and sevelamer) resulted in significantly lower serum phosphate as compared to placebo (moderate to very low quality of evidence). We found no statistically significant differences between active treatment categories in lowering serum phosphate. Sevelamer, lanthanum and diet resulted in lower serum calcium compared to calcium (moderate quality evidence for lanthanum and diet; low quality evidence for Sevelamer). Iron, sevelamer and calcium yielded lower parathyroid hormone levels as compared to lanthanum. Meta-regression analyses did not yield a statistically significant association between treatment effect and trial duration.

Discussion/conclusions: We found few differences between treatments in impact on phosphate and differences in parathyroid hormone. Relative to calcium, sevelamer, lanthanum and diet showed significant reduction in serum calcium from baseline. Treatment recommendations should be based on impact on patient-important outcomes rather than on surrogate outcomes. Systematic review registration: PROSPERO CRD-42016032945.

Fig 1. PRISMA flow diagram.

Fig 2. Risk of bias assessment for surrogate outcomes.

Fig 3. Network of clinical trials of phosphate binders in patients with chronic kidney disease: outcome mean change from baseline in serum phosphate concentration.

Netplot of effectiveness outcome for mean phosphate reduction at the end of the study period. Network of randomized controlled trials comparing different phosphate binders for mean change in serum phosphate. Lines connect different phosphate binder categories with direct evidence. The width of lines correlates the number of RCTs for each direct comparison while the size of the nodes correlates with the total sample size. Abbreviations: cal: calcium; calmag: calcium and magnesium; calsev: calcium and Sevelamer; calsevlant: calcium or sevelamer or lanthanum;lant: lanthanum; seve: Sevelamer.

Fig 4. Network meta-analysis results for serum phosphate.

Forest plot of effectiveness outcome for mean phosphate reduction at the end of the study period. MD: Mean difference; Crl: Credible interval; PrI: predictive intervals.

Fig 5. Rank-heat plot of the phosphate binder network for laboratory outcomes.

Fig 6. Network of clinical trials of phosphate binders in patients with chronic kidney disease: outcome mean change from baseline in serum calcium concentration.

Netplot of effectiveness outcome for mean calcium reduction at the end of the study period. Network of randomized controlled trials comparing different phosphate binders for mean change in serum calcium. Lines connect different phosphate binder categories with direct evidence. The width of lines correlates the number of RCTs for each direct comparison while the size of the nodes correlates with the total sample size. Abbreviations: cal: calcium; calmag: calcium and magnesium; calsev: calcium and Sevelamer; Lant: lanthanum; seve: Sevelamer.

Fig 7. Network meta-analysis results for serum calcium.

Forest plot of effectiveness outcome for mean calcium reduction at the end of the study period; MD: Mean difference; Crl: Credible interval; PrI: predictive intervals.

Fig 8. Network of clinical trials of phosphate binders in patients with chronic kidney disease: outcome mean change from baseline in serum parathyroid hormone concentration.

Netplot of effectiveness outcome for mean parathyroid hormone reduction at the end of the study period. Network of randomized controlled trials comparing different phosphate binders for mean change in serum parathyroid hormone Lines connect different phosphate binder categories with direct evidence. The width of lines correlates the number of RCTs for each direct comparison while the size of the nodes correlates with the total sample size. Abbreviations: cal: calcium; calmag: calcium and magnesium; calsev: calcium and Sevelamer; Lant: lanthanum; seve: Sevelamer.

Fig 9. Network meta-analysis results for serum parathyroid hormone.

Forest plot of effectiveness outcome for mean parathyroid hormone reduction at the end of the study period; MD: Mean difference; Crl: Credible interval; PrI: predictive interval.