Sevelamer versus calcium-based phosphate binders in chronic kidney disease: what should we conclude from the evidence to date?

Abstract

Calcium-based phosphate binders have traditionally been considered standard first-line treatment for control of hyperphosphataemia in chronic kidney disease (CKD). However, several cross-sectional studies have observed that prescribed calcium intake from phosphate binders is dose-dependently associated with the degree of vascular calcification in CKD patients [1,2]. Other studies have demonstrated an association between vascular calcification scores and an increased risk of cardiovascular disease [3– 5]. Although there is presently no proof that interventions that reduce the surrogate outcome of vascular calcification lead to reduced cardiovascular events in CKD patients, the K/DOQI guidelines have recommended that the ‘total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1500 mg/day (opinion), and the total intake of elemental calcium (including dietary calcium) should not exceed 2000 mg/day (opinion)’ [6]. If these guidelines are followed, there is likely to be a substantial shift in clinical practice away from the use of calciumbased phosphate binders to non-calcium-based phosphate binders, such as sevelamer, which are considerably more expensive. This raises the important question of just how good is the evidence that sevelamer therapy results in superior patient-level outcomes (i.e. ‘hard’ clinical end-points) compared with calcium-based phosphate binder therapy? To date, there has only been one randomized controlled trial (RCT) of sevelamer versus calcium-based binders, which has been adequately powered for mortality. The Dialysis Clinical Outcomes Revisited (DCOR) study involved 75 centres and 2103 haemodialysis patients randomly allocated to receive either sevelamer or a calcium-based phosphate binder for a mean follow-up period of ∼20 months [7]. Sevelamer-treated patients experienced comparable allcause mortality [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.79–1.10] and cardiovascular mortality (HR 0.93, 95% CI 0.74–1.17) to patients receiving calciumbased binders. Based on a significant interaction between the pre-specified variable of age and treatment effect (P = 0.02), a subsequent age-stratified analysis demonstrated that sevelamer was associated with a reduction in mortality in patients aged 65 years or older (HR 0.77, 0.61– 0.96). However, these results were limited by the fact that the authors did not correct their interaction assessments for multiple comparisons, which would have yielded a nonsignificant result. A subsequent intention-to-treat analysis of the DCOR study using pre-planned secondary analyses and Centers for Medicare & Medicaid Services data demonstrated no significant differences in overall or cardiovascular mortality and no significant interaction between age and treatment effect [8]. A meta-analysis of RCTs, including the DCOR study, observed that sevelamer treatment was associated with similar all-cause mortality (risk difference −2%, 95% CI −6%– 2%; 5 RCTs and 2429 participants) and cardiovascular mortality (risk difference −1%, 95% CI −4%–2%; 3 RCTs and 2102 participants) compared with calcium-based phosphate binder therapy [9]. The authors concluded that there was ‘no convincing evidence that sevelamer improves clinically relevant outcomes in ESRD patients’ and that ‘recommendations for the routine use of sevelamer in dialysis patients are not supported by current data.’ In this issue of Nephrology Dialysis and Transplantation, Jamal et al. report the results of an updated systematic review of the effects of calcium-based versus non-calciumbased phosphate binders on mortality in CKD patients [10]. Eight RCTs of sevelamer versus calcium-based binders were selected. The study was sponsored by Genzyme (manufacturers of sevelamer) and one of the authors declared a potential conflict of interest with Genzyme. Similar to the findings of the previous meta-analysis, Jamal et al. reported no significant differences between patients treated with sevelamer or calcium-based phosphate binders with respect to coronary artery calcification (WMD −76.35, 95% CI −158.25–5.55; 5 RCTs and 469 participants), cardiovascular events [relative risk (RR) 0.85, 95% CI 0.35– 2.03; two RCTs and 153 participants] or all-cause mortality (RR 0.68, 95% CI 0.41–1.11; eight RCTs and 2873 participants). In spite of the non-significant differences between the groups, the authors concluded that there were ‘trends’ towards decreased all-cause mortality, cardiovascular mortality and coronary artery calcification associated with noncalcium-based phosphate binders and that future studies are needed to conduct ‘research on the mechanism by which non-calcium-based phosphate binders reduce mortality or