Phosphorus Control
calcium based phosphate binders in calcification during the last decade. In brief, a series of clinical studies have evaluated this issue, involving between 90 and 200 CKD patients, comparing calcium-based phosphate binders with sevelamer-HCL with regard to the progression of CAC using techniques such as electron beam computer tomography. Some of these studies showed significantly reduced progression of CAC in patients receiving sevelamer-HCL compared with calcium-based phosphate binders after treatment periods of one to two years.19,41,42 These studies also showed reduced hypercalcaemia and total calcium score for sevelamer-HCL compared with calcium treatments. One other study that included 101 patients receiving HD, however, showed similar levels of CAC in calcium- versus sevelamer-HCL-treated patients and found no differences in bone remodelling.35
Sevelamer-HCL is also well
In the Calcium acetate (Phoslo®)/Sevelamer (Renagel®) evaluation 2 (CARE-2) study, including 203 patients with CKD patients receiving HD, serum LDL-C was controlled equally with atorvastatin in both study groups (sevelamer-HCL and a calcium-based phosphate binder over a one-year period).43
known to have a serum low-density cholesterol (LDL-C)-lowering effect.42
There was no difference in the
progression of CAC between the groups. Overall, both the KDIGO guidelines and the recent Cochrane analysis conclude that the role of calcium-based phosphate binders in soft tissue calcification remains a controversial issue.1,32
Other studies have investigated the benefits of calcium-based phosphate binders in terms of hospitalisation, patient outcomes, mortality and cost-efficacy, compared with the more recently introduced calcium-free phosphate binders, in particular sevelamer-HCL. The Dialysis clinical outcomes revisited (DCOR) study specifically addressed the issue of mortality; a comparison of sevelamer-HCL with calcium-based phosphate binders in 2,103 patients with stage 5D CKD revealed that there was no difference in the incidence of death between groups treated with sevelamer-HCL or a calcium-based phosphate binder. Only in a post-hoc analysis of patients over 65 years of age was there evidence for a survival benefit with sevelamer-HCL; a secondary analysis also found a trend towards reduction in all-cause hospitalisations over a follow-up period of up to 45 months.44,45
The Cochrane review of phosphate binders for treating bone disease in CKD concludes that the newer phosphate binders, such as sevelamer-HCL and lanthanum carbonate, have an unknown impact on morbidity and mortality.32
It also concludes that avoiding calcium-based
binding agents could theoretically reduce the risk of vascular calcification and cardiovascular disease. The review suggests that further research is needed to compare the effects of sevelamer-HCL, lanthanum carbonate and calcium salts on parameters including all-cause and cardiovascular mortality. The KDIGO guidelines state that there is a paucity of high quality studies evaluating the clinical benefit of treatments given to patients with CKD-MBD.1
KDIGO
recommend that research should determine which phosphate binders and other phosphate-lowering treatments are able to improve survival in patients with CKD stages 3–5D. This is a matter of great importance and urgency for the nephrology community worldwide, since we must be able to demonstrate patient benefit and cost-effectiveness in our management of CKD-MBD.
The cost effectiveness of the non-calcium phosphate binders is also controversial. These treatments are substantially more expensive than the traditional treatments and have yet to demonstrate overall advantages in reducing phosphate levels or reducing mortality. A health
96
economic evaluation in Canada on database information from a sample of 37 % of patients with CKD initiating renal replacement (n=7,034) showed that the incremental cost of sevelamer-HCL was C$17,000/patient (assuming no survival or hospitalisation advantage for sevelamer-HCL). The cost per quality-adjusted life year (QALY) was C$77,600 (excluding costs of dialysis and transplantation). The authors concluded this was not cost effective even in elderly patients for whom a lower mortality risk with sevelamer-HCL has been suggested.46
A
study in the UK, however, found that sevelamer-HCL had an incremental cost of £6,521 per sevelamer-treated patient over five years and increased with an incremental cost per quality-adjusted life year (QALY) of £27,120 and an incremental cost per life year gained of £15,508. It was concluded that the morbidity and mortality benefits of sevelamer-HCL justified the ‘modest’ investment.47
A recent
comparative study on 51 patients with CKD in Italy suggested that switching patients receiving HD from sevelamer-HCL to lanthanum carbonate enabled the National Kidney Foundation Disease Outcomes Quality Initiative (NKF-KDOQI)-recommended phosphate levels to be achieved with a significant (44 %, p<0.01) reduction in cost.48
Another
study showed that, in patients not adequately controlled using calcium carbonate as a phosphate binder, lanthanum carbonate was as cost-effective as second-line treatment, applying a cost-effectiveness threshold of £30,000 per QALY.49
The treatment model in the study was
that patients receiving lanthanum treatment as second-line treatment for a trial period who failed to meet guideline phosphate levels should be switched back to a calcium-based phosphate binder.
In the light of the existing evidence, calcium-based phosphate binders remain the first choice among the established phosphate binders in many health systems, although in the US, the majority of patients are started on sevelamer-HCL or lanthanum carbonate. However, it would seem prudent in patients with persistent hypercalcaemia, adynamic bone or known vascular calcification, to restrict calcium-based compounds in light of the available evidence. In CKD patients with serum calcium levels in the normal range, the evidence supporting the use of newer calcium-free phosphate binders is only moderate and these treatments are less justified in view of the high cost. Avoiding calcium-based binders has become normal practice at some treatment centres where the alternatives are affordable, but strong clinical data supporting this approach to CKD treatment is lacking. Additional important factors in the choice of phosphate binders are patient preference and adherence to prescribed therapy.50 These are at least as important as the efficacy of the treatment and should not be overlooked.
Considering Concomitant Therapies
When choosing a phosphate binder and the dose to administer to a patient receiving dialysis, it is important that a full assessment of concomitant therapies, such as the dose of vitamin D therapy and the concentration of calcium in the patient’s dialysate, is carried out. KDIGO guideline 4.1.4 addresses a formerly perceived general lack of consensus guidelines for these interrelated treatments.1,51
In a
cross-sectional analysis of a population of 5,100 patients with CKD and receiving HD at the Renal Research Institute in New York, only 14 % of the patients fell within the old KDOQI guidelines on both plasma phosphate and calcium, suggesting that treatments are failing to adequately control mineral balance in CKD.51
It has been suggested that some patients receiving HD continually experience calcium overload originating from the dialysate.52
Sigrist et al. EUROPEAN NEPHROLOGY
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