Sevelamer Linked to Lower Cardiovascular Death Risk in Patients on Hemodialysis

In a trial comparing the phosphorus binder sevelamer with calcium-containing phosphorus binding agents (PBAs), patients starting hemodialysis who used sevelamer had a much lower risk of cardiovascular (CV) events and all-cause death over the course of the study. Antonio Bellasi, MD, of the Ospedale Sant’anna in Como, Italy, presented the results of the open-label, randomized, controlled trial in May at the 49th European Renal Association–European Dialysis and Transplant Association Congress in Paris.

The study randomly assigned incident hemodialysis patients to sevelamer (232 patients) or to calcium-containing PBAs (234 patients). The researchers followed them until study completion or until death occurred.

The study population was about half men and had a mean age of 65 years. Hypertension was present in 79 percent, CV disease in 36 percent, and diabetes in 29 percent of patients at baseline.

Bellasi explained that the trial had to be open label because the physicians would know which patients were on sevelamer “because of the impact of sevelamer on lipids.” However, the investigators who analyzed the outcomes were blinded to which groups the patients were in.

Sevelamer linked to benefits on many outcome measures

After 36 months of follow-up, the patients using sevelamer had an 89 percent lower risk of CV-related mortality than the patients taking the calcium-containing PBA (relative risk [RR], 0.11, p < 0.001). There were nine CV-related deaths in the sevelamer group versus 79 in the calcium PBA group. When adjusted in a multivariate analysis for possible contributing factors, the RR remained 0.11, indicating that sevelamer use was an independent predictor of the much lowered risk.

Similarly, the sevelamer group did much better in terms of all-cause survival, with a greater than 70 percent reduction in the risk of all-cause death regardless of whether the RR was unadjusted or adjusted for various possible confounding factors. There were 28 deaths from any cause in the sevelamer group at 36 months compared with 100 deaths in the calcium-containing PBA group.

Sevelamer use was also linked to less progression of coronary artery calcification (CAC) when examined after 24 months of the study. At 12 months, half of the calcium PBA group had CAC progression whereas only one-fifth had progression in the sevelamer group (p < 0.001). At 24 months, CAC progression affected two-thirds of the patients on calcium-containing PBAs but slightly less than 40 percent of those taking sevelamer (p < 0.001).

It appeared that cardiac arrhythmias were a significant contributor to the CV deaths because sevelamer was associated with a 93 percent reduction in the risk of arrhythmias. Adjusting for other parameters yielded essentially the same result. The corrected QT interval remained fairly constant in the sevelamer group but somewhat prolonged over time for the patients assigned to a calcium-containing PBA (p < 0.001). Prolongation of the corrected QT interval can lead to arrhythmia.

Sevelamer did not appear to reduce the risk of death from non-CV causes, and its beneficial effect on all-cause mortality risk was most likely a result of its lowering the risk of CV mortality, which contributed to the all-cause mortality. Non-CV deaths—a secondary end point of the trial—were essentially no different at 36 months between the two groups. There were 19 deaths in the sevelamer group and 21 in the calcium-containing PBA group.

Bellasi concluded that the study lends support to the view that incident hemodialysis patients “may benefit greatly from treatment of hyperphosphatemia with use of the non–calcium containing phosphate binder sevelamer when compared to treatment with calcium-based binders.” The study was fairly large and was conducted long enough to see the effects of the treatments on CV events and mortality.

However, before the results can be accepted as conclusive and applied generally, some points need to be clarified. The chairman of the session in which the results were presented, David Goldsmith, MB, BChir, consultant nephrologist at Guy’s and St. Thomas’ Hospital in London, told Kidney News that he has questions about the level of compliance with therapy in the two treatment groups, and he would like to see data on hypercalcemic episodes as well as on mortality according to the levels of serum calcium and phosphate that were actually achieved.

Notes

[1] Dr. Bellasi has received honoraria from Genzyme, Amgen, and Sanofi, now the parent company of Genzyme. There was no commercial funding for the study. Dr. Goldsmith was not involved in the study. He has received research support from Genzyme, the maker of sevelamer, and is a consultant to Sanofi.


July 2012 (Vol. 4, Number 7)