A Comparison of Sevelamer and Calcium-Based Phosphate Binders on Mortality, Hospitalization, and Morbidity in Hemodialysis: A Secondary Analysis of the Dialysis Clinical Outcomes Revisited (DCOR) Randomized Trial Using Claims Data Wendy L. St. Peter, Jiannong Liu, Eric Weinhandl, and Qiao Fan AJKD 2008

Objective Secondary results of an intent-to-treat comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity end points by using CMS* data. * CMS: Centers of Medicare & Medical Services

Methods The CMS database includes data obtained from: The CMS ESRD medical evidence report (CMS-2728). The ESRD death notification form (CMS-2746). Medicare part A institutional claims (inpatient, outpatient, skilled nursing, home health, and hospice). Medicare part B physician (inpatient and outpatient) and supplier claims. The CRF database 1 was linked to the CMS ESRD database by the US renal data system (USRDS) coordinating center. Subjects were grouped by age (65 and 65 years), race (black and nonblack), and diabetes status (no diabetes, diabetes as ESRD cause, and diabetes as comorbid condition, but not ESRD cause). 1: CRF: Case Report Form - database used in Suki W. et al. KI 72: (2007)

Methods II Death was classified as cardiovascular, infection, and other. Hospitalizations were classified as cardiovascular, infection, vascular access, fracture, and other. Inclusion criteria: Mortality analysis: All subjects who could be linked to the CMS ESRD database were included in mortality analyses because the database contains death information for all patients with ESRD. Hospitalization and morbidity: Only subjects with Medicare as primary payor. Patient Follow-up: For mortality analyses, subjects were followed up from the randomization date to the earliest of date of death, kidney transplantation, modality change to peritoneal dialysis, or December 31, For hospitalization and morbidity analyses, subjects were followed up to the earliest of date of first event, death, transplantation, change in modality, early site closure, consent withdrawal, or December 31, 2004.

Results Patient Distribution

Results Early Discontinuation Overall, 970 of 2,101 patients discontinued early, based on CMS data and the 90-day follow-up rule from the original trial analysis. The probability of discontinuation because of adverse events was greater in the sevelamer group (7.5% versus 4.6% at trial conclusion) The probability of discontinuation because of investigator decision was greater in the calcium group (13.6% versus 8.2% at trial conclusion).

Results All-Cause and Cause-Specific Mortality During the follow-up period, 431 deaths were recorded for the sevelamer group, and 426 for the calcium group. Probability of all-cause mortality in the intent-to- treat population

Results All-Cause and Cause-Specific Mortality All-cause or cause-specific mortality rates were not significantly different between sevelamer and calcium group. Age x treatment interaction (without adjustment) was significant (p≤0.01). After Bonferroni adjustment for the 10 patients characteristics x treatment interactions tested, the interaction was not longer significant (p =0.06).

Results All-Cause and Cause-Specific Hospitalization and Hospital days Relative Risk Risk reduction 95% CIp All-cause hospitalization % Other-cause hospitalization % Hospital Days % Relative risk comparing Sevelamer and calcium groups

Results Cause-Specific Morbidity Subjects randomly assigned to sevelamer consistently showed lower risks of multiple morbidities; however, none of the differences was statistically significant.

Discussion Intent-to-treat analysis: The open-label nature of the DCOR study may have created an informative censoring issue. More calcium-group subjects discontinued early, and termination reasons were different between groups, possibly resulting in a biased population over time. An intent-to-treat approach solves this problem by following up subjects to the end of the study. However, after subjects discontinued the study, they could stop phosphate binder therapy (unlikely) or switch to an alternative binder or binder combination (more likely), resulting in a smaller treatment difference between groups.

Conclusions All-cause mortality rate did not differ between the sevelamer- or calcium-treated groups during a 3-year study period. Cause-specific mortality rates were not affected by treatment. Sevelamer use resulted in a 10% decrease in all-cause hospitalization rate and a 12% decrease in number of all-cause hospital days compared with calcium-based P-binder use.

Suki & ST. Peter SukiSt. Peter Patient DatabaseCRFCMS (part of the CRF database) Patients included in the analysis Sevelamer: 551 Calcium: 517 Mortality analysis: Sevelamer: 825 Calcium: 826 Morbidity/Hospitalization: Sevelamer: 491 Calcium: 502 Number of deaths Sevelamer: 267 Calcium: 275 Sevelamer: 431 Calcium: 426 All-cause MortalityNot statistically significant Age-treatment interaction -23% reduction risk in patients >65y in favor of sevelamer (p=0.02) No statistically significant age/treatment interaction was found All-cause Hospitalization Non-statistically significant trend favoring sevelamer (p=0.07) -10% reduction risk in favor of sevelamer (p=0.02) Hospital Days Non-statistically significant trend favoring sevelamer (p=0.09) -12% reduction risk in favor of sevelamer (p=0.03)