Secondary Hyperparathyroidism in Chronic Dialysis Patients: Results ...

Original Paper Received: August 10, 2010 Accepted: February 8, 2011 Published online: May 28, 2011

Blood Purif 2011;32:124–132 DOI: 10.1159/000325454

Secondary Hyperparathyroidism in Chronic Dialysis Patients: Results of the Italian FARO Survey on Treatment and Mortality Diego Brancaccio a Mario Cozzolino a Giuseppe Cannella b Piergiorgio Messa c Mario Bonomini d Giovanni Cancarini e Maria Rosa Caruso f Carmelo Cascone g Anna Maria Costanzo h Umberto di Luzio Paparatti h Sandro Mazzaferro i on behalf of the FARO Study Group

a

University of Milan, Milan, b Nephrology, San Martino Hospital, Genoa, c Nephrology, Policlinic Hospital, Milan, Nephrology, S.S. Annunziata Hospital, Chieti, e Nephrology, Spedali Civili and University, Brescia, f Nephrology, Ospedali Riuniti Hospital, Bergamo, g Nephrology, S. Maria dei Battuti Hospital, Treviso, h Abbott Italy, Campoverde, Latina, and i Clinical Science, Sapienza University, Rome, Italy

d

Abstract Introduction: Vitamin D receptor activator (VDRA) therapy has been shown to be associated with reduced mortality rates in chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT). However, differences between VDRAs in their ability to reduce both all-cause and cardiovascular-related mortality rates are not yet fully elucidated. Methods: The objective of the current analysis was to determine the effect of VDRA therapy on mortality in an Italian dialysis population, observed prospectively every 6 months for 18 months. Patients were investigated for allcause and cardiovascular-related mortality risk adjusted for various demographic, clinical, and/or SHPT treatment variables. Results: The cumulative probabilities of all-cause and cardiovascular-related mortality were lower for patients who received any VDRA treatment compared with those

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who did not (p ! 0.001) regardless of all measured variables. Additionally, patients who received paricalcitol and/or cinacalcet (with or without VDRAs) compared with calcitriol showed a significant improvement in both all-cause and cardiovascular-related mortality (p ! 0.001). Cinacalcet with or without VDRAs was not associated with a further decrease of mortality hazard ratios compared with paricalcitol monotherapy. Conclusions: VDRA therapy (associated or not with cinacalcet) was associated with improved survival in dialysis patients, independent of demographic and clinical variables. Copyright © 2011 S. Karger AG, Basel

Introduction

Chronic kidney disease (CKD) is often associated with low circulating levels of active vitamin D (i.e., 1␣,25-dihydroxyvitamin D3 (1,25-D)), as the kidney is the primary metabolic site for producing 1,25-D [1, 2]. This may generate serious implications for CKD patients because Diego Brancaccio, MD Nephrology Unit, University of Milan c/o Dialysis Unit Simone Martini Via Simone Martini 24, IT–20143 Milan (Italy) Tel. +39 02 8912 4311, E-Mail diego.brancaccio @ tiscalinet.it

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Key Words Dialysis ⴢ Calcitriol ⴢ Cinacalcet ⴢ Paricalcitol ⴢ Secondary hyperparathyroidism

Methods The FARO survey was a multicenter survey of treatment practices (from April 2006 to October 2007) in 28 dialysis centers representative of the Italic peninsula. Briefly, patient questionnaires were completed at each center over an 18-month period (baseline, months 6, 12, and 18) and subsequently reviewed and approved by the physician in charge. Therapy for CKD-MBD management was prescribed without any influence by the FARO steering committee and prescription of calcitriol, paricalcitol and/or cinacalcet was usually dictated by the severity of SHPT considering also the best serum Ca and P control. The survey was designed so patients could enter or exit a given dialysis center over the course of the 18-month study, resulting in varying sam-

FARO Survey – Mortality

ple sizes for each of the 4 surveys due to various reasons (e.g., new patient, death, or transfer to another center). Patients provided written informed consent and the study was in compliance with the local ethical committees. Mortality Risk Assessments All-cause and cardiovascular-related mortality risks by treatment type (i.e., oral or intravenous (IV) calcitriol, IV paricalcitol, or cinacalcet with or without concomitant VDRAs) were assessed using a time-dependent model among all patients at each postbaseline session (i.e., months 6, 12, and 18). Mortality risk hazard ratio (HR) assessments for VDRA and/ or cinacalcet therapy versus no therapy factored in adjustments for various demographic and clinical values, including comorbidities (hepatic, vascular, or other); sex; history of diabetes; age (^50, 150 to ^64, 1 64 to ^74, and 675 years); serum hemoglobin levels (^10 and 110 g/dl); serum albumin levels (^3.5, 13.5 to ^3.9, and 13.9 g/dl); serum PTH levels (^150, 1150 to ^300, and 1300 pg/ml); serum Ca levels (^8.4, 18.4 to ^9.5, and 19.5 mg/dl), and serum P levels (^3.5, 13.5 to ^5.5, and 15.5 mg/dl). Crude and adjusted time to all-cause and cardiovascular-related mortality HRs were assessed for each treatment group versus no treatment and were adjusted for various demographic and clinical values, including sex, age (per 10-year increase), comorbidities, and history of diabetes. Time-dependent variables included erythropoietin use, serum hemoglobin, serum albumin, serum PTH (^150 vs. 1150 to ^300, and 1300 pg/ml); serum Ca (^8.4 vs. 18.4 to ^9.5, and 19.5 to ^10.5 mg/dl), and serum P (^3.5 vs. 13.5 to ^5.5, and 15.5 mg/dl). Statistical Analyses The cumulative probability of all-cause and cardiovascularrelated death was estimated using the Kaplan-Meier method among patients included in the first study session and stratified by treatment (i.e., none, calcitriol, paricalcitol, or cinacalcet with or without other VDRAs). If a patient switched treatments, the risk time for him/her was divided into specific time contributions depending on when treatment changed. However, a patient remained in a given treatment cohort if his/her therapy was interrupted or discontinued without starting another treatment for SHPT. The Cox proportional hazard regression model was used to estimate crude and adjusted time to all-cause and cardiovascular-related mortality HRs. Three dummy time-dependent variables for each 6-month time period were used to estimate the mortality HR of each treatment compared with no treatment (i.e., data from a given patient may have been used in different treatment groups if that patient began, stopped, or switched treatment during the study). In order to determine if the effect of treatment type varied in different subgroups, stratified analyses were performed. Within each level of the stratified variables, the analysis adjusted for all the potential confounders included in the multiple model. All Cox proportional hazard regression models were stratified by each participating clinical center. Statistical analyses were performed using SAS (version 8.2 per WindowsTM, Cary, N.C., USA) and STATA (version 8.0, College Station, Tex., USA) software.

Blood Purif 2011;32:124–132

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vitamin D plays critical roles in maintaining mineral homeostasis such as regulation of calcium (Ca) absorption, maintenance of skeletal density, inhibition of parathyroid hormone (PTH) production, and regulation of phosphorus (P) metabolism, which has the potential to significantly affect vascular structure and function [3, 4]. As such, maintaining vitamin D sufficiency is important for ensuring optimal health. Interestingly, excessive exogenous 1,25-D treatment (i.e., calcitriol) can lead to abnormally elevated serum Ca and P profiles that have been associated with an increased risk of morbidity (e.g., vascular calcification) and subsequent mortality [5, 6]. In an effort to maximize the beneficial aspects of 1,25-D while minimizing the risks associated with calcitriol treatment, several synthetic vitamin D receptor activators (VDRAs) have been developed [3, 7–9]. As the mainstay of treatment for secondary hyperparathyroidism (SHPT) in dialysis patients [10, 11], vitamin D therapy has been significantly associated with a reduction in all-cause [12–14] and cardiovascular-related mortality rates [13, 15–18]. More recently, data from the prospective Accelerated Mortality on Renal Replacement (ArMORR) study – showing that low circulating levels of 25-dihydroxyvitamin D3 and 1,25-D were associated with increased all-cause and cardiovascular mortality [19] – also indicated that survival was significantly improved in patients receiving VDRA therapy compared with untreated patients [19, 20]. More interestingly, even in patients with less severe stages of CKD (i.e., stage 3–5) not yet on hemodialysis, calcitriol administration was associated with a significant survival advantage [21, 22]. The aim of this prospective study has been to assess the potential relationship among the available therapies for SHPT and outcomes (including cardiovascular morbidity and mortality) in RDT patients.

Characteristic

n = 2,378

Sex, n (%) Male Female Age, years (mean8SD) Years of dialysis treatment (mean8SD) Laboratory values (mean8SD) PTH, pg/ml Ca, mg/dl P, mg/dl Ca!P, mg2/dl2 Hemoglobin, g/dl Albumin, g/dl Use of erythropoietin, n (%) Comorbidity, n (%) Hypertension Heart disease Vascular disease Dyslipidemia Diabetes Liver disease Neoplasia

1,478 (62) 900 (38) 65814 586 307.98288.3 9.180.8 5.181.4 45.7813.3 11.381.4 3.680.8 2,119 (89) 1,584 (67) 1,092 (46) 674 (28) 445 (19) 356 (15) 233 (10) 112 (5)

Ca = Calcium; P = phosphorus; PTH = parathyroid hormone.

Results

Disposition, Demographics, and Laboratory Characteristics Out of 2,637 patients initially included in the study, 2,378 were included in the current analysis. A total of 259 patients were excluded for the following reasons: 206 (7.8%) were lost to follow-up after participating in a single survey period; 41 (1.6%) received treatment other than oral or IV calcitriol, IV paricalcitol, or cinacalcet, and 12 (0.5%) were deceased prior to the first study session. Sample sizes for each of the four 1-week sessions varied based on changes in patient exit and entry over the 18-month period (baseline, n = 2,230; month 6, n = 2,316; month 12, n = 2,268; month 18, n = 2,106). Patients had a mean age of 65 years and had received hemodialysis treatment for an average of 5 years (table 1). Outside of elevated baseline PTH levels (mean 307.9 pg/ml), Ca, P, and Ca ! P levels were within K/DOQI target ranges. In addition, a large proportion of patients demonstrated comorbid conditions, particularly cardiovascular-related conditions. By month 18, K/DOQI target measurements for serum levels of PTH, Ca, P, and all three combined were achieved in 32.0, 55.9, 55.1, and 11.5% of all patients, respectively. 126

Blood Purif 2011;32:124–132

Survival: Unadjusted Analyses The cumulative risk of all-cause and cardiovascularrelated deaths were significantly lower over the course of the survey for patients who received treatment compared with untreated patients (p ! 0.001; fig. 1). An assessment between treatments showed that patients who received paricalcitol or cinacalcet (with or without VDRAs) compared with calcitriol also experienced a significant improvement in all-cause and cardiovascular-related mortality (p ! 0.001; fig. 1). No significant differences were noted when comparing paricalcitol and cinacalcet (with or without VDRAs) in all-cause (p = 0.39) or cardiovascular-related (p = 0.60) mortality. Although a significant difference was noted between paricalcitol and calcitriol for all-cause (p = 0.01) and cardiovascular-related (p ! 0.04) mortality, calcitriol compared with no treatment also showed a significant improvement over no treatment for both mortality measures (p ! 0.01). Survival: Effect of Demographic and Clinical Variables VDRA treatment was associated with numerically lower all-cause and cardiovascular-related mortality HRs regardless of adjustments for all measured demographic and clinical variables (fig. 2). Oral or IV calcitriol, IV paricalcitol, and cinacalcet (with or without VDRA treatment) were all associated with statistically significant reductions in crude and adjusted time to death HRs versus no treatment (tables 2–4). In adjusted analyses, increasing age and a history of vascular disease or neoplasia were associated with statistically significant increases in timeto-death HRs for all-cause mortality (table 2). A slight variation was noted for cardiovascular-related mortality, with increases noted in adjusted time to death HRs for increasing age, history of heart disease or vascular disease, and Ca ! P (table 3).

Discussion

Collectively, results from the FARO survey suggest that treatment for SHPT is associated with reduced overall and cardiovascular-related probabilities of death as well as factor-adjusted mortality risks among Italian dialysis patients with SHPT. As expected, patients who received no treatment had a poorer prognosis than those who did. Survival data from the current analysis also suggest that paricalcitol is associated with an improvement over calcitriol for lowering the risk of overall and cardiovascular-related death. These findings were also Brancaccio et al.


Table 1. Patient demographics and baseline characteristics

*

Probability of all-cause mortality (%)

30 No treatment Calcitriol Paricalcitol Cinacalcet with/without VDRAs 20

†

10

0

a

0

Treatment (n) No treatment Calcitriol Paricalcitol Cinacalcet with/without VDRAs

942 947 288 199

Probability of cardiovascularrelated mortality (%)

30

Fig. 1. Patient survival. The cumulative probability of all-cause (a) and cardiovascular-related (b) mortality are presented


18

820 824 341 207

305 304 189 111

593 649 322 230

No treatment Calcitriol Paricalcitol Cinacalcet with/without VDRAs

20

* †

10

0

b Treatment (n) No treatment Calcitriol Paricalcitol Cinacalcet with/without VDRAs

0 942 947 288 199

6 12 Time after enrollment (months)

18

820 824 341 207

305 304 189 111

Blood Purif 2011;32:124–132

593 649 322 230

127


for patients who received no VDRA treatment, calcitriol, paricalcitol, or cinacalcet with or without VDRA treatment. Significance for all-cause mortality was p ! 0.01 for calcitriol vs. no treatment, p = 0.01 for paricalcitol vs. calcitriol, and p = 0.39 for cinacalcet vs. paricalcitol. Significance for cardiovascular-related mortality was p ! 0.01 for calcitriol vs. no treatment, p ! 0.04 for paricalcitol vs. calcitriol, and p = 0.60 for cinacalcet vs. paricalcitol. * p ! 0.001: no treatment vs. calcitriol, paricalcitol, and cinacalcet with or without VDRA treatment groups; † p ! 0.001: calcitriol vs. paricalcitol and cinacalcet with or without VDRA treatment groups.

6 12 Time after enrollment (months)

Variable

Variable Male Female Age ≤50 years Age >50 and ≤64 years Age >64 and ≤74 years Age ≥75 years PTH ≤150 pg/ml PTH >150 and ≤300 pg/ml PTH >300 pg/ml Calcium ≤8.4 mg/dl Calcium >8.4 and ≤9.5 mg/dl Calcium >9.5 mg/dl Phosphorus ≤3.5 mg/dl Phosphorus >3.5 and ≤5.5 mg/dl Phosphorus >5.5 mg/dl Albumin ≤3.5 g/dl Albumin >3.5 and ≤3.9 g/dl Albumin >3.9 g/dl Hemoglobin ≤10 g/dl Hemoglobin >10 g/dl Diabetic Nondiabetic Comorbidities: vascular Comorbidities: hepatic Comorbidities: other

a

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 All-cause HR Favors VDRA therapy Favors no therapy

Male Female Age ≤50 years Age >50 and ≤64 years Age >64 and ≤74 years Age ≥75 years PTH ≤150 pg/ml PTH >150 and ≤300 pg/ml PTH >300 pg/ml Calcium ≤8.4 mg/dl Calcium >8.4 and ≤9.5 mg/dl Calcium >9.5 mg/dl Phosphorus ≤3.5 mg/dl Phosphorus >3.5 and ≤5.5 mg/dl Phosphorus >5.5 mg/dl Albumin ≤3.5 g/dl Albumin >3.5 and ≤3.9 g/dl Albumin >3.9 g/dl Hemoglobin ≤10 g/dl Hemoglobin >10 g/dl Diabetic Nondiabetic Comorbidities: vascular Comorbidities: hepatic Comorbidities: other

b

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Cardiovascular-related HR Favors VDRA therapy Favors no therapy

Fig. 2. Mortality risk: demographic and clinical subsets. Effects of VDRA treatment alone (not including cinacalcet) on all-cause (a) and cardiovascular-related (b) mortality risk (i.e., HR) are presented for patients in different demographic and clinical subsets (note: in a, the upper 95% CI for the ^50 age group exceeds the range

of the figure).

128

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mains to be confirmed in a prospective randomized clinical trial. The current analysis was not designed to assess how specific VDRA dosing regimens affected patient mortality rates; however, it is important to consider dosage ranges when discussing mortality data to determine clinical relevance. As previously reported, patients in the current study received weekly mean doses of oral calcitriol, IV calcitriol, or IV paricalcitol that ranged from 1.9–2.2, 3.4– 3.7 to 11.2–15.9 ␮g, respectively, depending on the study visit. Previous work suggests that these VDRA doses are comparable or higher than those reported here and are capable of providing significant clinical benefit in hemodialysis patients [12, 15, 24]. In a time-dependent, 2-year, prospective analysis of patients on maintenance hemodialysis therapy (n = 58,058), Kalantar-Zadeh et al. [12] showed that even lower doses of paricalcitol (1–4.99 ␮g/ week) were associated with reductions in all-cause mortality HRs. Using a subset of patients (n = 34,307) from the same database in a similar analysis, hemodialysis patients who received an average weekly dose of IV paricalBrancaccio et al.


found by Teng et al. [23] who performed a large (n = 67,399) retrospective analysis that showed a significantly lower mortality rate among hemodialysis patients receiving IV paricalcitol compared with those receiving IV calcitriol. Additionally and more importantly, patients receiving paricalcitol who switched to calcitriol had significantly higher mortality rates than those receiving calcitriol who switched to paricalcitol; the overall survival advantage attributed to paricalcitol over calcitriol was 16% [23]. In another retrospective database analysis by Tentori et al. [14] (n = 7,731), mortality rates were also significantly lower among hemodialysis patients treated with paricalcitol (or doxercalciferol) compared with those treated with calcitriol (p ! 0.05). More recently, Tentori et al. [24] compared the different methods for evaluating the clinical impact of vitamin D and observed that previously published Dialysis Outcomes and Practice Patterns Study (DOPPS) data [25] could have been distorted by possible unmeasurable confounders. Therefore, the advantage of vitamin D treatment on survival in patients on hemodialysis re-

Table 2. Crude and adjusted time to all-cause mortality hazard ratios

Variable

Treatment vs. no treatment Oral and IV calcitriol Paricalcitol Cinacalcet with or without VDRAs Age (per 10-year increase) Dialysis duration (per 10-year increase) Sex (female vs. male) Comorbidity/treatment history (yes vs. no) Hypertension Dyslipidemia Heart disease Neoplasia Liver disease Vascular disease Diabetes Use of erythropoietin Hemoglobin (per 1 g/dl increase) Albumin (per 1 g/dl increase) PTH, pg/ml ≤150 vs. >150 to 300 >300 to 700 vs. >150 to 300 >700 vs. >150 to 300 Ca, mg/dl ≤8.4 vs. 8.4 to 9.5 >9.5 to 10.5 vs. 8.4 to 9.5 >10.5 vs. 8.4 to 9.5 P, mg/dl ≤3.5 vs. >3.5 to 5.5 >5.5 vs. >3.5 to 5.5 Ca!P>55 vs. ≤55 mg2/dl2

Mortality HR (95% CI) crude

adjusted

0.57 (0.46–0.71)* 0.31 (0.22–0.44)* 0.23 (0.15–0.37)* 1.59 (1.46–1.74)* 0.94 (0.80–1.10) 0.91 (0.75–1.09)

0.63 (0.50–0.79)* 0.43 (0.29–0.63)* 0.36 (0.22–0.58)* 1.41 (1.27–1.55)* 1.14 (0.96–1.36) 1.10 (0.90–1.35)

0.69 (0.55–0.85)* 0.74 (0.58–0.93)* 1.55 (1.25–1.92)* 2.32 (1.77–3.03)* 1.08 (0.82–1.40) 2.10 (1.72–2.55)* 1.30 (1.03–1.65)† 1.44 (0.87–2.39) 0.68 (0.63–0.73)* 0.31 (0.27–0.37)*

0.74 (0.58–0.93)* 0.90 (0.70–1.15) 1.13 (0.90–1.43) 1.60 (1.20–2.13)* 1.22 (0.92–1.63) 1.28 (1.03–1.59)† 1.28 (0.99–1.65) 0.93 (0.55–1.58) 0.48 (0.40–0.58)* 0.77 (0.71–0.84)*

1.29 (1.03–1.62)† 0.81 (0.62–1.04) 0.91 (0.57–1.44)

0.94 (0.74–1.20) 0.99 (0.75–1.30) 1.45 (0.89–2.38)

1.54 (1.23–1.94)* 0.93 (0.72–1.20) 1.10 (0.60–2.02)

1.21 (0.95–1.54) 1.16 (0.88–1.52) 1.30 (0.67–2.49)

1.97 (1.47–2.65)* 1.23 (0.98–1.55) 0.80 (0.62–1.03)

1.15 (0.78–1.69) 1.03 (0.75–1.42) 1.23 (0.84–1.80)

citol (14.3 ␮g/week) – comparable to that of patients in the current study – also experienced significant reductions in the relative risk of death compared with patients who were untreated [24]. A recent historical large cohort study of chronic hemodialysis patients in Latin American dialysis sites supports the significant overall survival benefit of oral active VDRA (97% calcitriol) using a mean daily dose as high as 0.51–1 ␮g and as low as !0.25 ␮g over no VDRA therapy [15]. To our knowledge, this FARO data analysis includes the only available prospective data concerning mortality risk in hemodialysis patients receiving calcimimetics.

The data indicate that paricalcitol and cinacalcet (only a few patients were treated with cinacalcet alone, at baseline and during the 18-month period of follow-up) treatment groups experienced reduced overall and cardiovascular-related probabilities of death compared with no treatment and calcitriol treatment groups. Why the expanded use of specific VDR-selective agonists or calcimimetics? It could be argued that the recently progressive clinical use of new compounds (paricalcitol and/or cinacalcet) could represent a greater degree of concern by the clinician to actively manage CKD-MBD. Due to low sample sizes, patients who received cinacalcet treatment without a VDRA were not assessed by


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Ca = Calcium; CI = confidence interval; HR = hazard ratio; IV = intravenous; P = phosphorus; PTH = parathyroid hormone; VDRA = vitamin D receptor activator. * p ≤ 0.01, † p < 0.05.

Table 3. Crude and adjusted time to cardiovascular-related mortality hazard ratios

Variable

Mortality HR (95% CI)

Treatment vs. no treatment Oral and IV calcitriol Paricalcitol Cinacalcet with or without VDRAs Age (per 10-year increase) Dialysis duration (per 10-year increase) Sex (female vs. male) Comorbidity/treatment history (yes vs. no) Hypertension Dyslipidemia Heart disease Neoplasia Liver disease Vascular disease Diabetes Use of erythropoietin Hemoglobin (per 1 g/dl increase) Albumin (per 1 g/dl increase) PTH, pg/ml ≤150 vs. >150 to 300 >300 to 700 vs. >150 to 300 >700 vs. >150 to 300 Ca, mg/dl ≤8.4 vs. >8.4 to ≤9.5 >9.5 to 10.5 vs. >8.4 to 9.5 >10.5 vs. >8.4 to 9.5 P, mg/dl ≤3.5 vs. >3.5 to ≤5.5 >5.5 vs. >3.5 to ≤5.5 Ca !P >55 vs. ≤55, mg2/dl2

crude

adjusted

0.67 (0.49–0.91)* 0.38 (0.23–0.63)* 0.29 (0.15–0.53)* 1.52 (1.34–1.71)* 0.99 (0.79–1.23) 0.91 (0.70–1.20)

0.69 (0.50–0.95)† 0.40 (0.23–0.68)* 0.36 (0.19–0.69)* 1.36 (1.19–1.56)* 1.15 (0.90–1.46) 1.08 (0.81–1.43)

0.84 (0.60–1.16) 0.94 (0.68–1.30) 2.02 (1.47–2.78)* 0.75 (0.42–1.35) 0.84 (0.56–1.27) 2.58 (1.94–3.43)* 1.53 (1.11–2.11)* 0.92 (0.52–1.64) 0.81 (0.72–0.90)* 0.43 (0.33–0.54)*

0.83 (0.59–1.17) 0.99 (0.70–1.40) 1.51 (1.08–2.12)† 0.63 (0.35–1.15) 0.92 (0.60–1.42) 1.63 (1.19–2.23)* 1.32 (0.92–1.88) 0.66 (0.36–1.22) 0.61 (0.45–0.82)* 0.85 (0.76–0.96)*

1.23 (0.87–1.73) 1.15 (0.81–1.63) 1.16 (0.61–2.18)

0.98 (0.69–1.40) 1.31 (0.91–1.90) 1.72 (0.88–3.38)

1.56 (1.12–2.17)* 1.03 (0.72–1.46) 1.29 (0.58–2.85)

1.39 (0.98–1.97) 1.18 (0.81–1.71) 1.36 (0.59–3.17)

1.46 (0.95–2.24) 1.02 (0.75–1.39) 1.19 (0.86–1.66)

1.39 (0.78–2.50) 1.26 (0.78–2.05) 2.14 (1.25–3.65)*

Ca = Calcium; CI = confidence interval; HR = hazard ratio; IV = intravenous; P = phosphorus; PTH = parathyroid hormone; VDRA = vitamin D receptor activator. * p ≤ 0.01, † p < 0.05.

Treatment

Time after enrollment, months 0–6

No treatment Calcitriol Paricalcitol Cinacalcet with or without VDRAs Total

130

Total

6–12 12–18

85 39 7 6

88 59 22 7

71 46 11 9

244 144 40 22

137

176

137

450

Blood Purif 2011;32:124–132

themselves and it is impossible to decipher the effect cinacalcet treatment per se may have had on reducing mortality risk independent of concomitant VDRA therapy. A previous retrospective combined analysis of four randomized, double-blind studies indicated that patients receiving cinacalcet had significantly lower rates of parathyroidectomy, fracture, and cardiovascular-related hospitalization compared with those receiving placebo [26]. However, the impact of cinacalcet on mortality has not been conclusively established, as all-cause hospitalization and mortality rates in patients receiving cinacalcet were similar to those receiving placebo, and some patients in this study also received a VDRA concomitantly [26]. Brancaccio et al.


Table 4. Deaths by type of treatment and time after enrollment


on the other hand, cinacalcet, alone or in combination with any VDRAs, evaluated in a limited subset of patients did not appear to be associated with additional benefit to what was already observed in paricalcitol-treated patients. Finally, it should be underlined that the validity of these data needs to be confirmed in future prospective randomized studies.

Acknowledgements The authors would like to thank the FARO Study Group: Vittorio Emanuele Andreucci (Napoli), Guido Bellinghieri (Messina), Roberto Bigazzi (Livorno), Piergiorgio Bolasco (Quartu S. Elena), Marina Di Luca (Pesaro), Giuseppe Emiliani (Ravenna), Loreto Gesualdo (Foggia), Cosimo Lodeserto (Taranto), Luigi Lombardi (Catanzaro), Fabio Malberti (Cremona), Martino Marangella (Torino), Massimo Morosetti (Ostia Lido), Giovanni Panzetta (Trieste), Deni Aldo Procaccini (Foggia), Mario Procida (Potenza), Francesco Quarello (Torino), Giuseppe Rombolà (La Spezia), Maurizio Salvadori (Firenze), Francesco Paolo Schena (Bari), and Sergio Stefoni (Bologna). We would also like to thank Brett Mahon, PhD, for his assistance in preparing the manuscript; this assistance was funded by Informa Srl. An unrestricted educational grant for this study was provided by Abbott Srl Italy.

Disclosure Statement D. Brancaccio – FARO Steering Committee, lecture honoraria from GSK, Abbott, Amgen and Shire; M. Cozzolino – lecture honoraria from Abbott, Shire, Amgen; S. Mazzaferro – FARO Steering Committee; lecture fees from Shire and Amgen; P. Messa – FARO Steering Committee; lecture fees from Amgen; G. Cannella: FARO Steering Committee; honoraria for lectures: Abbott, Janssen Cilag, Amgen; A.M. Costanzo – Abbott Italy Medical Manager; U. di Luzio Paparatti – Abbott Italy Medical Director; M. Bonomini – none; G. Cancarini – lecture fees from Boehringer Ingelheim and Roche; a Research grant by Roche; M.R. Caruso – none; Carmelo Cascone – lecture fees from Shire and Abbott.

References

1 Tentori F: Focus in vitamin D therapy in chronic kidney disease. J Nephrol 2007; 20: 511–514. 2 Martin KJ, Gonzales EA: Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol 2007; 18:875–885. 3 Cozzolino M, Gallieni M, Brancaccio D, et al: Vitamin D retains an important role in the pathogenesis and management of secondary hyperparathyroidism in chronic renal failure. J Nephrol 2006; 19:566–577.

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Block et al. [27] in a recent retrospective study showed that cinacalcet was associated with improved cardiovascular and all-cause survival in a large cohort of hemodialysis patients. However, even in this study there still remains the same concern about the possible role of cinacalcet on survival when used in combination with VDRAs. Approximately two-thirds of all patients in the FARO study failed to achieve target PTH levels and nearly 90% failed to achieve combined target PTH, P, and Ca levels as described by the K/DOQI guidelines [28], which indicates that the achievement of K/DOQI target ranges may be difficult for many CKD patients with SHPT. Reassessment of K/DOQI target ranges may be warranted to determine if they are perhaps too strict and this prompted to consider new target as reported in K-DIGO Guidelines. However, the impact on survival is clear; VDRA therapy (specifically when patients were treated with paricalcitol) was significantly associated with a reduced risk of all-cause and cardiovascular-related mortality among all FARO survey patients collectively. Adding cinacalcet, a significant benefit was also reported in comparison to the patients treated with calcitriol (or no therapy), but no statistical advantage was observed in comparison to those who were treated with paricalcitol. There were several limitations to the FARO survey, including less than ideal sample sizes, variable durations of treatment between patients, and a generally heterogeneous patient population. Although sample sizes varied between treatment groups, a minimum of 111 patients were included in each treatment group at each 6-month time point of the survival analysis, which is not insignificant. In spite of the relatively short period of observation (i.e., 18 months), we were able to show significant differences in patient mortality risk between treatment groups with trends suggesting that more robust differences may have been evident if a larger sample size and a longer observation period had been evaluated. The lack of standardization regarding therapy allowed for a relatively heterogeneous, non-randomized patient population including both prevalent and incident dialysis patients, and precluded the ability to compare specific dosing regimens within treatment groups. As noted above, these data also report the first prospective evaluation of survival in hemodialysis patients receiving cinacalcet (with or without VDRAs). In conclusion, these data indicate that VDRAs are associated with a decrease in all-cause and cardiovascular-related death in hemodialysis patients and that paricalcitol treatment was associated with a clear improvement over calcitriol;

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