Administered paricalcitol dose and survival in hemodialysis patients: A marginal structural model analysis

Abstract

Purpose Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients. However, patients with higher serum parathyroid hormone (PTH), a surrogate of higher death risk, are usually given higher VDRA doses, which can lead to confounding by indication and attenuate the expected survival advantage of high VDRA doses. Methods We examined mortality-predictability of low (>1 but <10 μg/week) versus high (≥10 μg/week) dose of administered paricalcitol over time in a contemporary cohort of 15,442 MHD patients (age 64±15 years, 55% men, 44% diabetes, 35% African Americans) from all DaVita dialysis clinics across the USA (7/2001-6/2006 with survival follow-ups until 6/2007) using conventional Cox regression, propensity score (PS) matching, and marginal structural model (MSM) analyses. Results In our conventional Cox models and PS matching models, low dose of paricalcitol was not associated with mortality either in baseline (hazard ratio (HR): 1.03, 95%confidence interval (CI): (0.97-1.09)) and (HR: 0.99, 95%CI: (0.86-1.14)) or time-dependent (HR: 1.04, 95%CI: (0.98-1.10)) and (HR: 1.12, 95%CI: (0.98-1.28)) models, respectively. In contrast, compared to high dose of paricalcitol, low dose was associated with a 26% higher risk of mortality (HR: 1.26, 95%CI: (1.19-1.35)) in MSM. The association between dose of paricalcitol and mortality was robust in almost all subgroups of patients using MSMs. Conclusions Higher dose of paricalcitol appears causally associated with greater survival in MHD patients. Randomized controlled trials need to verify the survival effect of paricalcitol dose in maintenance hemodialysis patients are indicated.

Vitamin D receptor activator and prevention of cardiovascular events in hemodialysis patients—rationale and design of the Japan Dialysis Active Vitamin D (J-DAVID) trial

“…According to a recent meta-analysis [45], there are only weak and imprecise correlations of drug effects on serum levels of phosphate, calcium, and PTH with all-cause and cardiovascular death in patients with CKD, suggesting that the drug's nonmineral actions favorably affected these clinical endpoints. The same has been suggested also by previous cohort studies in which the use of VDRAs [16][17][18][19][20][21] or the use of phosphate-binders [21,46] were associated with a lower risk of all-cause death, CVD death, or incident CVD in dialysis patients, even after adjusted for serum calcium, phosphate, and PTH levels. The J-DAVID study will reveal whether or not the VDRA treatment reduces CVD and/or mortality even when the current target ranges of phosphate, calcium, and intact PTH are respected.…”

“…The use of activated vitamin D sterols, or vitamin D receptor activators (VDRAs), was reported to be associated with lower risk of all-cause mortality [16][17][18], CVD-related mortality [19,20], and incident CVD [21] in hemodialysis patients. Many, but not all [22], studies reported such associations as previously reviewed [23].…”

Mortality of combined serum phosphorus and parathyroid hormone concentrations and their changes over time in hemodialysis patients

“…In previous studies, vitamin D analogs therapy was associated with favorable outcomes in CKD [29, 30] and dialysis patients. [31–33] Active vitamin D therapy may impact outcomes independently of its effect on serum PTH. Patients having persistent high serum PTH tended to be continuously treated with high dose of active vitamin D, which could attenuate a harmful effect from uncontrolled serum PTH.…”

Dose of Hemodialysis and Survival: A Marginal Structural Model Analysis

“…The percentages of patients censored for kidney transplantation and being loss to follow-up were 4% and 2%, respectively. The use of one set of censoring weights has been performed in the previous studies [21, 22]. Sensitivity analyses were conducted with consideration of censoring weights for transplantation, and loss to follow-up.…”