Not baseline but time-dependent erythropoiesis-stimulating agent responsiveness predicts cardiovascular disease in hemodialysis patients receiving epoetin beta pegol: A multicenter prospective PARAMOUNT-HD Study.

Background: Responsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown.
Methods: This multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF).
Results: The median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03-2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14-2.23), MACE (HR: 1.60, 95% CI: 1.19-2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40-2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23-3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI.
Conclusions: Baseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.
Competing Interests: Declaration of Competing Interest H. F. received speaker fees as honoraria from Chugai and Kyowa Kirin, advisory board fees as honoraria from Chugai, and scholarship grants from Chugai and Kyowa Kirin. T. H. received speaker fees as honoraria from Chugai, Kyowa Kirin, Kissei, Ono, Torii, Otsuka, Bayer, Asahi Kasei and Astellas; grants from Chugai, Kyowa Kirin, Kissei, Ono, Torii, Otsuka, Terumo, Fuso, Bayer, Asahi Kasei, Eisai, and Takeda; advisory board fees as honoraria from Kyowa Kirin, Ono, Glaxo SmithKline and Astellas. K. T. received speaker fees as honoraria from Chugai, Kyowa Kirin, Otsuka, Ono and Bayer; grants from Chugai, Kyowa Kirin, Otsuka, Ono, Kissei, Baxter and Tanabe Mitsubishi; and advisory board fees as honoraria from Chugai, Kissei, and Sanwa. T. K. received speaker fees as honoraria from Chugai and Kyowa Kirin. N. J. received speaker fees as honoraria from Chugai, Kyowa Kirin and Torii, and grants from Chugai, Kyowa Kirin and Torii. K. T. received speaker fees as honoraria from Chugai and Kyowa Kirin and grants from Chugai and Kyowa Kirin. H. H. received speaker fees as honoraria from Chugai, Kissei, Torii, Tanabe Mitsubishi and Astellas. Y. U. received speaker fees as honoraria from Chugai. K. N. received speaker fees as honoraria from Chugai and Kyowa Kirin and grants from Chugai and Kyowa Kirin.
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