Phosphate Binder for Dialysis May Lower Mortality Rates in Older Patients

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Phosphate Binder for Dialysis May Lower Mortality Rates in Older Patients
   
By Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
August 31, 2007
   
      
   MedPage Today Action Points

    * Explain to patients that kidney dialysis is associated with hyperphosphatemia, which is treated with a phosphate-binding agent.

    * Point out that this study was unable to demonstrate a difference in mortality between patients treated with sevelamer compared with calcium-based phosphate binders but there was a suggestion that sevelamer was associated with lower overall mortality in patients older than 65.

   
   Review
HOUSTON, Aug. 31 -- For older patients on dialysis, the phosphate binder sevelamer (Renagel) may be associated with a lower death rate compared with calcium-based phosphate binders, investigators reported.

However, in a randomized trial pitting sevelamer against calcium-based phosphate binders for prevention of hyperphosphatemia in dialysis patients, the study did not meet its primary endpoint of demonstrating a statistically significant mortality benefit (P=0.40).

There were no overall significant differences in all-cause or cause-specific mortality for those randomized to Renagel compared with those treated with calcium-based phosphate binders, found Wadi N. Suki, M.D., of Baylor College of Medicine here, and colleagues.

Only in patients older than 65 was there a significant effect of sevelamer in lowering the mortality rate, they reported online in Kidney International. "There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients," they wrote.

Sevelamer, a non-abosrbed, phosphate-binding polymer, has been shown in previous studies to be associated with lower degrees of arterial calcification than calcium-based binders. But whether the reduction in calcification might translate into lower mortality rates among dialysis patients had been unknown, the authors noted.

They conducted a multicenter, randomized, open-label trial in 2,103 patients on kidney dialysis in 75 U.S.centers. A total of 1,068 patients completed the study, 551 in the sevelamer group, and 517 in the calcium group. The calcium binders used were either calcium acetate (PhosLo), or calcium carbonate (Tums) for those patients who could not tolerate calcium acetate.

The patients were followed from randomization date through either death, study cessation, in the case of early termination, 90 days following discontinuation of the study drug. The primary endpoint was all-cause mortality; cause-specific mortality, including deaths from cardiovascular events, infections, or other causes, was a secondary endpoint.

Deaths were classified as being cardiovascular if they occurred because of acute myocardial infarction, pericarditis (including cardiac tamponade), atherosclerotic heart disease, cardiomyopathy, cardiac arrhythmia, cardiac arrest (cause unknown), valvular heart disease, pulmonary edema due to exogenous fluid, cerebrovascular accident (including intracranial hemorrhage), or ischemic brain damage/anoxic encephalopathy.

The investigators also looked at hospitalization and discharge dates, demographics, and renal history data.

In all-cause mortality, there were 267 deaths in the sevelamer group and 275 deaths in the calcium group. The sevelamer-group mortality rate was 15.0 per 100 patient-years, compared with 16.1/100 in the calcium group (hazard ratio 93, 95% confidence interval 0.79 to .10; log-rank P=0.40).

A Kaplan-Meier survival analysis curve showed no difference in mortality risk for patients who were on study for less than two years.

"However, for those patients remaining on study for at least two years (43% of the population), a difference between groups, favoring sevelamer, appears to emerge (time-treatment interaction P=0.02)," the authors wrote.

Similarly, there were no significant overall differences between the treatment groups in cause-specific mortality. In all, 53% of deaths were attributable to cardiovascular causes, with a mortality rate of 8.0 per 100 patient-years among patients on sevelamer, and 8.6 per 100 patient years among patients on calcium (hazard ratio 93, 95% CI, 0.74 to 1.17, log-rank P=0.53).

There were 47 deaths from infection in the sevelamer (rate 2.6 per 100 patient-years) and 41 in the calcium group (rate 2.4 per 100 patient-years, log-rank P=0.68). There were 78 deaths from other causes among patients on sevelamer (rate 4.4/100 patient-years) vs. 87 deaths among patients on calcium (rate 5.1/100 patient-years, log-rank P=0.33).

When, in a prespecified analysis, they looked at deaths by age category, they found that there was a significant interaction between treatment type and all-cause mortality, but not cause-specific mortality.

The all-cause mortality rate among patients 65 and older (44% of all patients) was 18.2 per 100 patient-years for the sevelamer group and 23.4 per 100 patient-years for the calcium group (hazard ratio 77, 95% CI, 0.61 to 0.96, P=0.02).

Among patients less than 65, however, there was no difference in all cause mortality (P=0.21), and there was no difference in the interaction between age and treatment type for cardiovascular mortality, the authors found.

Among patients 65 and older, the cardiovascular mortality rate for those on sevelamer was 10.5 per 100 patient-years compared with 13.3 per 100 patient-years for those on calcium (hazard ratio78, 95% CI, 0.58-1.05). Among patients younger than 65, the cardiovascular death rate was 6.1 per 100 patient-years and 5.1 per 100 patient years, respectively (hazard ratio 1.19, 95% CI, 0.82-1.73).

"The findings in older subjects are consistent with earlier literature documenting that older hemodialysis patients tend to have greater calcification burden than younger patients," the investigators wrote. "Therefore, it may be that a calcium effect on mortality could occur over a shorter follow-up time in older as compared with younger patients."

"Furthermore, progression of calcification is greater among those patients with higher levels of arterial calcification at baseline. Although not statistically significant, the potential benefit in younger subjects treated with calcium-based binders deserves further investigation," they wrote.

They noted that the study was limited by the open-label design and by the 46% dropout rate. "While there were no differences in the time to discontinuation among subjects who discontinued early, there remains the possibility that some unmeasured factors could have introduced additional bias," they wrote.

Genzyme Corporation, maker of sevelamer, funded the study and wrote the protocol. Dr. Suki has received research grants and honoraria from the company.
Primary source: Kidney International
Source reference:
Suki WN et al. "Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients." Kidney International 2007; doi:10.1038/sj.ki.5002466.
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