Sevelamer hydrochloride

In 2007 Tonelli et al engaged in a systematic review by comparing the use of sevelamer hydrochloride vs. calcium-based phosphate binders and combining data from 2,501 participants in 10 randomized clinical trials (Nephrol Dial Transplant. 2007; 22:2856-2866). Results showed that phosphate levels were consistently lower in the calcium-based binder group.

It is important to note that higher sevelamer doses such as those used in certain trials, e.g., the Renagel in New Diagnosis study (RIND) (Kidney Int. 2007;71:438-441), can lower phosphate to levels comparable to those achieved by calcium-based binders. No statistically significant difference in serum calcium-phosphate product levels was found between calcium-based binders and sevelamer in the 2007 review.

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As expected, there were fewer episodes of hypercalcemia in the sevelamer group for an absolute risk that was 21% lower (95% CI: 13-29) than for those on calcium-based binders. Mean parathyroid hormone levels were lower in those on calcium-based binders, and serum bicarbonate levels were lower by 2.8 mmol/L with sevelamer hydrochloride therapy.

Patient outcomes

Several randomized clinical trials have compared the effects of sevelamer hydrochloride vs. calcium-based binders on patient outcome. Of the studies evaluating calcification scores, the Treat to Goal study (Kidney Int. 2002;62:245-252) and the RIND study both showed less CAC in the sevelamer group, but it was unclear if the CAC difference was due to a reduced calcium load or to lower LDL levels in the sevelamer group.

To address the potential LDL effect, the Calcium Acetate Renagel Evaluation-2 (CARE-2) study randomized participants to atorvastatin plus either sevelamer or calcium acetate to achieve an LDL less than 70 mg/dL (Am J Kidney Dis. 2008;51:952-965); 97% of those on calcium acetate were on atorvastatin compared with 79% of the sevelamer hydrochloride group. While it is hard to make comparisons between these groups because of the multiple potential pleiotropic effects of atorvastatin, no difference in calcification scores was found between the two treatment arms.

Furthermore, it is important to note that CARE-2 was the only study to show increased calcification scores in the sevelamer hydrochloride group. The high discontinuation rate and numerous crossovers in the trial would bias the results toward the null, suggesting a potential reason for the lack of differences seen in the trial.

The Dialysis Clinical Outcomes Revisited (DCOR) trial, the largest study on this subject, randomized 2,103 HD patients to receive either calcium-based binders or sevelamer hydrochloride (Kidney Int. 2007;72:1130-1137). In the 1,068 patients who completed the study, there were 267 deaths in the sevelamer hydrochloride group and 275 deaths in the calcium-based binder group for a hazard ratio of 0.93 (95% confidence interval: 0.79-1.10). A benefit to sevelamer therapy was observed in those patients 65 years and older.

In the RIND study, after a median 44 months of follow-up, those randomly assigned to calcium-based phosphate binders experienced a hazard ratio of 3.1 (95% CI: 1.23-7.61) for mortality compared with those assigned to sevelamer. Several differences in the two studies may explain the different overall findings.

The RIND study enrolled incident dialysis or new-to-dialysis patients and followed them for a longer period of time, while patients in the DCOR study had been on dialysis for a median of 24 months at the beginning of the trial. It may be that in prevalent dialysis patients, who most likely already have calcification, there is no benefit to sevelamer therapy. Interestingly, patients 65 years and older, who experienced a potential benefit in DCOR, also had a shorter duration of dialysis compared with those younger than 65.

It is hard to reconcile the theoretical benefits of noncalcium-based binders and the mostly negative clinical trial results. One possibility is that sevelamer hydrochloride may have other effects that obviate the potential for mortality benefit; for example, sevelamer hydrochloride causes a metabolic acidosis, and some studies suggest that low serum bicarbonate levels or systemic acidosis are associated with higher mortality (Am J Kidney Dis. 2004;44:661-671). Research into the use of sevelamer carbonate may be informative.