Abstract
Background and Aims
Hemodialysis (HD) patients hyporesponsive to erythropoiesis stimulating agents (ESAs) were reported to have poor prognosis. However, little is known regarding the association between the hyporesponsiveness to CERA and the types of outcome in HD patients. Moreover, the effect of on-line HDF on hyporesponsiveness to CERA has not been evaluated so far.
Method
In this multicenter prospective study, we enrolled 4034 maintenance HD patients receiving any kinds of ESA. Prior ESA was changed to CERA in all patients. We studied the association between erythropoietin resistance index (ERI) at 6-month after the change to CERA (baseline ERI) and such outcomes as cardiovascular events and/or mortality using Cox proportional hazards models (landmark analyses). ERI was defined as monthly CERA dose divided by hemoglobin and dry weight. Just before the enrollment of the patients, iron-based phosphate binders became available and on-line hemodiafiltration (HDF) began to be reimbursed in Japan, therefore, we examined whether oral iron-containing drugs and on-line HDF had some effects on the serial trend of ERI by mixed effects model with time-dependent ERI as a dependent variable. When ERI is found to be improved by these changes in practice patterns, we further studied the effect of time-dependent ERI on such outcomes as cardiovascular events, mortality, death due to cancer, and death due to infection by using marginal structural models to eradicate time-dependent confounding by iron parameters, C-reactive protein, iron-containing drugs, and HDF. Missing values were imputed by multiple imputations.
Results
Mean age was 65.9 years and 43.1% of patients had diabetes. The median dialysis vintage and observation period was 5.0 years and 22.1 months, respectively. The percentage of patients receiving oral iron-containing drugs increased from 11.1% at baseline to 25.0% at 24-month. As a result, mean TSAT level increased from 24.5% to 27.4% at 24-month. The percentage of patients on on-line HDF also increased from 13.5% to 22.6%. ERI gradually decreased as time went by with great improvement especially in patients with highest quintile of ERI (Q5). Mixed effects model with time-dependent ERI as a dependent variable showed that introduction of iron-containing drugs and on-line HDF had improved ERI significantly. The landmark analyses including 3001 patients failed to show significant associations between baseline ERI quintile and cardiovascular events or mortality. We only found that highest quintile of baseline ERI (Q5) was associated with significantly higher composite events of mortality and cardiovascular events as compared to the lowest quintile (Q1) (Hazard ratio [HR], 1.56; 95% CI; 1.04-2.32). However, marginal structural models showed that time-dependent ERI Q5 was significantly associated with higher cardiovascular event rate as compared to Q1 (HR, 2.11; 95% CI; 1.31-3.38). Trend toward higher rate of mortality with the increase in time-dependent ERI quintile was also observed (HR of Q5, 3.07; 95% CI; 1.95-4.83). Similar but stronger relationships were observed for death due to infection (HR of Q5, 6.70; 95% CI; 1.89-23.77) and death due to cancer (HR of Q5, 15.08; 95% CI; 4.08-55.74).
Conclusion
The prevailing use of iron-containing drugs and on-line HDF has improved hyporesponsiveness to CERA in Japan. Therefore, baseline ERI at 6-month did not predict subsequent cardiovascular events or death. However, high time-dependent ERI was a predictor of cardiovascular events, death due to infection, and death due to cancer as well as all-cause mortality. Strong association of time-dependent ERI was observed especially with death due to cancer.
Editorial: Observational Studies, Time-Dependent Confounding, and Marginal Structural Models
