Visual Abstract
Abstract
Background and objectives In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D3) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol.
Design, setting, participants, & measurements We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation.
Results A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0–5.5 mg/dl, and iPTH 150–600 pg/ml) were comparable between groups (45% versus 45%; P=0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences.
Conclusions Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.
- Mineral Bone Disorder
- calcium
- phosphate
- parathyroid hormone
- adult
- humans
- United States
- paricalcitol
- 1 alpha-hydroxyergocalciferol
- calcitriol
- cinacalcet
- phosphates
- length of stay
- survival rate
- retrospective studies
- follow-up studies
- intention to treat analysis
- ergocalciferols
- dihydroxy-vitamin D3
- Vitamin D
- secondary hyperparathyroidism
- renal dialysis
- minerals
- calcium phosphates
Introduction
Secondary hyperparathyroidism is a common occurrence in patients with ESKD. Hypersecretion of parathyroid hormone (PTH) occurs because of insufficient production of the biologically active form of vitamin D by the kidney and the resultant hypocalcemia. Active vitamin D is the standard of care for the management of secondary hyperparathyroidism. In the United States, intravenous (IV) administration of vitamin D analogs has been the default route of administration for treatment of secondary hyperparathyroidism in patients on maintenance hemodialysis, presumably influenced by studies suggesting that, in contrast to oral vitamin D, IV vitamin D was associated with fewer episodes of hypercalcemia and hyperphosphatemia and improved bone outcomes (1,2).
Despite these reports, subsequent studies in this population have revealed no difference in the control of PTH levels when comparing IV vitamin D to oral calcitriol (1,25-dihydroxyvitamin D3) therapy (3–5). These later comparison studies were limited by small numbers of patients, and meaningful outcomes such as hospitalizations and mortality were not examined in detail. Our primary goal was to examine mineral and bone disorder laboratory parameters in adults with ESKD receiving in-center hemodialysis who switched from an IV vitamin D analog to in-center oral calcitriol.
Materials and Methods
Study Cohort
We conducted a retrospective cohort study of patients with ESKD receiving in-center maintenance hemodialysis at Fresenius Kidney Care facilities who switched from an IV vitamin D analog (IV doxercalciferol or paricalcitol) to in-center administered oral calcitriol between December 1, 2013 and May 31, 2014. We restricted the study to patients who had received at least 30 administrations of an IV vitamin D analog (IV doxercalciferol or paricalcitol) in the 3 months before patients were identified as changing to oral calcitriol or matched, and to adults (18–100 years of age) who had a body mass index (BMI) between 15 and 60 kg/m2, and dialysis vintage ≤25 years (Figure 1). Among patients who met these criteria, 184 (7.4%) were excluded from the oral calcitriol cohort and 11,104 (5.5%) were excluded from the comparison cohort because of missing information on calcium, phosphorus, intact parathyroid hormone (iPTH), albumin, systolic BP, BMI, race, ethnicity, and/or vascular access type.
Cohort construction. BMI, body mass index; IV, intravenous.
Patients who switched to oral calcitriol during one of three sequential 2-month periods (December 2013– January 2014, February– March 2014, and April– May 2014) were matched 1:1 to patients on an IV vitamin D analog who did not switch during these intervals or any time prior. We used exact matching on sex, race, ethnicity, vascular access, ESKD network, and propensity score with nearest neighbor matching without replacement for age, vintage, BMI, comorbidities, and 3-month averages of postdialysis systolic BP, calcium, albumin, phosphate, and iPTH. Patients who served as controls during any prior 2-month period were not included as candidates for future matching. Data for patients during the three distinct periods were then combined into a single data set for analysis. The study entry criteria was on the basis of administration of IV doxercalciferol, IV paricalcitol, or oral calcitriol and concurrent administration of IV calcitriol was not considered for study entry or examined during follow-up. Utilization of IV calcitriol was overall rare, with ≤1% of the study cohort receiving any IV calcitriol during the baseline and ≤1% of the study cohort receiving any IV calcitriol during the follow-up periods. Assignment to the oral calcitriol or the IV vitamin D group was on the basis of in-center medication administration and <5% of patients in either the in-center administered oral calcitriol or IV vitamin D analog group also had oral calcitriol documented on their home medication list.
The start of observation was the date of the switch to oral calcitriol (oral calcitriol index date) or, for the comparison group on an IV vitamin D analog at the time of matching, it was the first day after the end of each 2-month evaluation period (IV vitamin D analog index date). For example, for patients who switched to oral calcitriol between December 1 and January 31, the oral calcitriol index date was the date oral calcitriol was first administered whereas for the matched cohort in this period, the IV vitamin D analog index date was February 1.
We followed patients from the index date to the earliest date of transfer to another dialysis facility, discharge from the clinic, loss to follow-up, recovery of kidney function, transplant, withdrawal from dialysis, death, or 12 months. The latest follow-up date was May 31, 2015.
Data Elements
Using the Fresenius Medical Care North America clinical data warehouse, we collected baseline data on the index date or, for certain variables, over the course of 3 months before the index date: age; sex; race; ethnicity; BMI; vascular access type; dialysis vintage; ESKD network; coexisting illnesses ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification codes including presence of coronary artery disease, cerebrovascular disease, heart failure, peripheral arterial disease, chronic obstructive pulmonary disease, and diabetes mellitus; and 3-month averages of postdialysis systolic BP, albumin, calcium, phosphate, and iPTH concentrations.
We sought to primarily examine monthly and 3-month averages of calcium and phosphate and 3-month averages of iPTH. Secondarily, we examined 12-month hospitalizations and mortality. All laboratory tests were performed in a centralized laboratory (Spectra Laboratories, Rockleigh, NJ and Milpitas, CA).
Statistical Analyses
We assessed the quality of matching using mean standardized differences. Our primary analysis was conducted using the intention-to-treat (ITT) approach during follow-up. Specifically, those who switched to oral calcitriol between December 1, 2013 and May 31, 2014 were compared with those who were receiving an IV vitamin D analog on the index date, acknowledging that patients could change therapy during follow-up. For months 1–3, 4–6, and 7–12, we compared the percentage of patients with mean laboratory values within range using the chi-squared test and compared the mean calcium, phosphate, and iPTH concentrations using the t test. Patients were classified in-range if their mean laboratory values were as follows: calcium≤10 mg/dl, phosphate 3 to ≤5.5 mg/dl, and/or iPTH 150 to ≤600 pg/ml. For these analyses, no missing laboratory values were imputed.
We compared cumulative hospitalization rates at 3, 6, and 12 months using Poisson regression. Hospital length of stay was truncated at 30 days. Cumulative survival at 3, 6, and 12 months was compared using Kaplan–Meier estimates and Cox proportional hazards models.
We performed additional analyses including (1) changes in calcium, phosphate, or iPTH among patients with complete laboratory values (i.e., at least one value within the prespecified time interval) using Cochran test to compare between time intervals within each group; and (2) an as-treated analysis of calcium, phosphate, or iPTH concentrations consisting of patients on IV doxercalciferol or paricalcitol during the enrollment period who did not switch to oral calcitriol, and oral calcitriol patients who did not switch back to IV doxercalciferol or paricalcitol in the ensuing 12 months from their index date. The as-treated analysis excluded patients who were receiving oral cinacalcet on or after their index date. The as-treated analysis did not account for whether IV calcitriol was administered during follow-up.
Lastly, we examined the doses of IV vitamin D and oral calcitriol during follow-up. First, to calculate the dose per treatment, we included patients who received only IV doxercalciferol or oral calcitriol during the interval of interest (e.g., 1–3, 4–6, and 7–12 months). We divided the sum of the doses in micrograms by the count of hemodialysis treatments in the period. We excluded patients receiving IV paricalcitol (doxercalficerol accounted for more than 90% of IV vitamin D analog use during the follow-up period). Our goal was to compare laboratory changes in patients who switched from an IV vitamin D analog to oral calcitriol, rather than to evaluate differences between vitamin D analogs. Second, to specifically examine changes in oral calcitriol doses during the follow-up, we restricted the cohort to patients who received oral calcitriol and did not receive IV doxercalciferol or paricalcitol for the entire follow-up period and examined how many of these patients had changes in the administered dose of calcitriol (up- or down-titration) or did not receive in-center oral calcitriol administration for >30 days.
All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC), and the study was approved by New England IRB, study number 120170009, and conducted in adherence with the Declaration of Helsinki.
Results
Baseline Characteristics
Our cohort included 4560 patients on maintenance hemodialysis in 18 ESKD networks. Nearly half (49%) of the patients were treated in the Southern Atlantic states of Alabama, Mississippi, and Tennessee. The overall cohort demographics were mean age of 61 years, 42% female, and 57% black. The prevalence of comorbidities, average postdialysis systolic BPs and baseline mineral and bone disorder parameters were similar between the two groups (Table 1).
Demographics and baseline characteristics of hemodialysis patients in oral calcitriol and IV vitamin D analog groups
Mineral and Bone Disorder Parameters
We examined calcium, phosphate, and iPTH concentrations after conversion to oral calcitriol compared with an IV vitamin D analog. For each, we calculated monthly and 3-month average values before the conversion dates. Monthly calcium and phosphate concentrations differed between the oral calcitriol and IV vitamin D groups (Figure 2) and the mean calcium and phosphate concentrations were lower over the follow-up period in those who switched from IV vitamin D to oral calcitriol (Table 2); information on the completeness of laboratory data are shown in Supplemental Table 1. Interestingly, the percent of patients in the oral calcitriol versus the IV vitamin D analog groups with average calcium levels that exceeded 10.2 mg/dl differed: 1–3 months, 2.4% versus 6.0% (P<0.01); 4–6 months, 2.4% versus 4.7% (P<0.01); and 7–12 months, 2.0% versus 3.1% (P=0.01), respectively. After the switch, mean iPTH levels were higher in the oral calcitriol group (Figure 2, Table 2). Although the average iPTH levels for the oral calcitriol group did not appear to exceed 600 pg/ml, the percent of patients in the oral calcitriol versus IV vitamin D group that had average iPTH values above 600 pg/ml differed: 1–3 months, 25% versus 18% (P<0.01); 4–6 months, 28% versus 20% (P<0.01); and 7–12 months 26% versus 22% (P=0.01), respectively.
Mean calcium, phosphorus, and iPTH concentrations differed between the oral calcitriol as compared toIV vitamin D analog group during follow-up. Bars indicate ±1 SD. iPTH, intact parathyroid hormone.
Comparison of calcium, phosphate, and parathyroid hormone concentrations between oral calcitriol and IV vitamin D analog groups during follow-up
We examined the proportion of patients whose laboratory values were within prespecified ranges at discrete time intervals (Table 3). We included all patients with available data in the time interval being examined, namely, even those who may have been missing a calcium, phosphate, or iPTH value within the other time intervals. The proportion of patients with laboratory values within the predefined ranges in months 1–3 largely persisted throughout the 12-month follow-up period. Importantly, the composite of calcium, phosphate, and iPTH values within range was 45% in both groups in the last follow-up period (P=0.96).
Comparison of calcium, phosphate, and intact parathyroid hormone concentrations within prespecified ranges between oral calcitriol and IV vitamin D analog groups during follow-up
We then restricted our analyses to patients with at least one laboratory value of each parameter during all three time intervals and re-examined the proportion of patients with values within the prespecified ranges over time (Supplemental Table 2). Again, the proportion of patients within each category at months 1–3 largely dictated the proportions observed during months 4–6 and 7–12, reaffirming that the proportion of patients whose laboratory parameters within target ranges within each group did not markedly fluctuate during follow-up.
We also performed an as-treated analyses, excluding individuals (1) receiving cinacalcet on or after their index date, (2) in the IV vitamin D analog group who switched to oral calcitriol, or (3) in the oral calcitriol group who switched back to an IV vitamin D analog during follow-up (analysis cohort for oral calcitriol, n=1271 and IV vitamin D analog, n=1001). Similar to the results presented in Table 3, the proportion of patients whose composite laboratory values were within prespecified ranges at 7–12 months did not significantly differ between groups (Supplemental Table 3). Finally, the use of cinacalcet was proportionally similar at baseline; however, the proportions changed over time (Supplemental Table 4).
Lastly, we performed two analyses, examining doses of IV doxercalciferol and oral calcitriol. The doses of both appeared to be higher over the ensuing 12 months (Supplemental Tables 5 and 6), and the relative change in dose during follow-up was higher for the oral calcitriol group. We examined doxercalciferol doses excluding those who used paricalcitol or oral calcitriol in the follow-up period. Likewise, to examine doses of oral calcitriol, we excluded those who also received IV doxercalciferol or paricalcitol during the follow-up. During the 12-month follow-up, 1722 (83%) of 2074 patients who received oral calcitriol for the entirety of the follow-up had their dose of calcitriol changed or not administered in-center for >30 days.
Hospitalizations and Mortality
Hospitalizations per patient-year were similar between groups in the 3 months before the index date (oral calcitriol, 0.92; IV vitamin D analog, 0.95), as were the length of hospitalization days per patient-year (oral calcitriol, 4.95; IV vitamin D analog, 4.80). We then compared the cumulative rates per patient-year of hospital admissions and hospital days between the two groups during the follow-up periods (Table 4). There were no intervals in which the rate of hospitalizations or lengths of stay differed significantly between the two groups.
Cumulative hospital admissions and length of stay at specified time intervals during follow-up
We examined 12-month survival between the two groups using Kaplan–Meier estimates (Figure 3) and observed no differences (log-rank P=0.79). The cumulative hazard rates of death comparing the oral calcitriol group to the IV vitamin D analog group were 0.94 (95% confidence interval, 0.63 to 1.41) at 3 months; 1.08 (95% confidence interval, 0.80 to 1.45) at 6 months; and 1.03 (95% confidence interval, 0.84 to 1.25) at 12 months. Furthermore, excluding patients who were receiving oral cinacalcet on their index date, we found that hospitalization and mortality rates were no different (data not shown).
Kaplan–Meier estimates showing no difference in survival in patients on oral calcitriol compared with intravenous vitamin D analog. Patient number denoted for each timepoint for oral calcitriol (red font) and intravenous vitamin D (blue font). Oral, oral calcitriol; IV, intravenous vitamin D.
Discussion
We sought to evaluate mineral and bone disorder parameters in patients on hemodialysis receiving care throughout the United States who switched from an IV vitamin D analog to oral calcitriol. Although we observed short-term changes in calcium, phosphate, and iPTH levels, the proportion of patients with all three parameters within ranges comparable with Kidney Disease Improving Global Outcomes targets (6) were largely similar between the two groups. Overall, switching from IV vitamin D analog to in-center oral calcitriol did not appear to result in clinically meaningful differences in biochemical parameters in the oral calcitriol as compared with the IV vitamin D analog group. Secondarily, hospitalizations and mortality rates also appeared to be similar between groups.
In the United States, IV vitamin D became the primary route of administration for management of secondary hyperparathyroidism in patients receiving maintenance dialysis after reports that, in contrast to oral administration, IV administration was associated with fewer episodes of hypercalcemia and hyperphosphatemia, better adherence, and improved bone outcomes (1,2). Other studies evaluating the efficacy of oral versus IV vitamin D examined primarily short-term treatment effects and found no differences in iPTH levels (1,4,5,7,8). A recent study examined the efficacy and safety of patients on maintenance hemodialysis previously receiving IV paricalcitol who then switched to oral calcitriol (9). At 5 months, the mineral and bone disorder parameters were comparable with levels that had been achieved before the switch. Finally, some longer-term studies have suggested that parenteral therapies were associated with improved outcomes (1,7,8). Limitations of past studies included small sample sizes, short-term follow-up, and importantly, inclusion of patients who at baseline were already being treated differently. Our study overcame many of these limitations, was of considerable sample size, and baseline characteristics were matched.
Our population was comparable to those patients on maintenance hemodialysis who were receiving therapy to manage secondary hyperparathyroidism (10). Approximately 60% of patients in both groups were black, a population known to have a higher frequency of secondary hyperparathyroidism. At baseline, iPTH values were between 300 and 400 pg/ml, and iPTH values rose in the oral calcitriol group. Although more of the oral calcitriol users had iPTH values that exceeded a threshold of 600 pg/ml (as recommended by Kidney Disease Improving Global Outcomes [6]), outcomes between the two groups did not appear to differ. We examined doses of one of the IV vitamin D analogs and oral calcitriol and found that over time, doses of each increased. Furthermore, the frequency of oral cinacalcet use also appeared to increase, and the increase appeared to differ between the groups. It is possible that clinicians decided to use additional oral cinacalcet among oral calcitriol users to better control iPTH. Consistent with these changes, oral calcitriol patients were less likely to have hypercalcemia. Notably, in the as-treated analysis that excluded patients using cinacalcet, we did not observe any distinctions in iPTH and calcium between groups at 7–12 months of follow-up.
Observational studies like ours have limitations, including potential for bias and residual confounding; however, observational studies contribute to the medical literature and can inform clinical practice and future studies. That said, patients in our study were switched from an IV vitamin D analog to oral calcitriol on the basis of clinicians’ preference, and not because of a randomized assignment. Therefore, we could not eliminate potential for selection bias. Although we performed a rigorously matched analysis, and baseline values used in our matching algorithms were obtained while all participants were still receiving IV vitamin D, confounding owing to unmeasured factors remain. In particular, clinical outcomes may be confounded by unmeasured facility-level effects, given the relatively early transition to calcitriol in this study. Furthermore, results could have varied depending on the matched comparison group. The primary ITT analysis could have been confounded by changes in vitamin D analogs and calcimimetics during the follow-up period. The primary ITT analysis, however, yielded consistent results for biochemical parameters to the as-treated analysis, which was restricted to patients who used the same route of vitamin D administration and were not administered a calcimimetic during follow-up. We further applied the inclusion requirement of at least 30 in-center IV vitamin D analog administrations during the 3 months preceding follow-up, thus selecting patients without prolonged hospitalization. Indeed, the rate of hospitalizations in this study was lower than that reported in the general in-center hemodialysis population (approximately 1.7 hospitalizations per year) (11). Our study was not designed to evaluate differences between vitamin D analogs, as these have been studied in the past (12–14) and the aggregate results suggest no material differences in outcomes, regardless of the type of analog used.
In summary, in this retrospective study of patients with ESKD from throughout the United States, switching from an IV vitamin D analog to oral calcitriol, compared with treatment with an IV vitamin D analog, the aggregate of all mineral and bone parameters in range was largely similar between the two groups.
Disclosures
Dr. Dalrymple, Dr. Hymes, Dr. Ofsthun, Dr. Rosen, and Dr. Usvyat are employees of Fresenius Medical Care North America. Dr. Maddux is an employee of Fresenius Medical Care AG & Co., KGaA. Dr. Dalrymple, Dr. Hymes, Dr. Maddux, Dr. Ofsthun, and Dr. Usvyat report share options and/or ownership in Fresenius Medical Care. Dr. Dalrymple reports that her spouse owns shares in The Permanente Medical Group and stock in Bayer and CVS. Dr. Hymes reports a position as a consultant for Nephroceuticals outside of the submitted work. Dr. Maddux reports directorships in American National Bank & Trust and a position as chairman of Pacific Care Renal Foundation, a 501(c)(3) nonprofit, outside of the submitted work. Dr. Thadhani was employed by Cedars-Sinai Medical Center at the time of completing this manuscript and reports that he is a consultant for Biogen Idec, Celgene, Fresenius Medical Care North America, Pfizer, Bayer, and Shire Human Genetics.
Funding
Dr. Thadhani is supported by research funding from the National Institutes of Health, Kaneka Corp., and Thermo Fisher Scientific.
Acknowledgments
We would like to acknowledge Eric D. Weinhandl for critical review of this manuscript, as well as John W. Larkin for contributions in the formatting and review of this manuscript. We would also like to acknowledge Susan Everson for her contributions to the formatting of the tables and figures.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.07960719/-/DCSupplemental.
Supplemental Table 1. Availability of biochemical measures in oral calcitriol and IV vitamin D analog groups during baseline period and follow-up.
Supplemental Table 2. Calcium, phosphate, and parathyroid hormone concentrations within pre-specified ranges in oral calcitriol and IV vitamin D analog groups over time.
Supplemental Table 3. As-treated comparison of calcium, phosphate, and parathyroid hormone concentrations within prespecified ranges between oral calcitriol and IV vitamin D analog groups during follow-up.
Supplemental Table 4. Percent of oral calcitriol and IV vitamin D analog patients receiving cinacalcet at baseline, and over the ensuing 12 months.
Supplemental Table 5. Dose of IV doxercalciferol during follow-up.
Supplemental Table 6. Dose of oral calcitriol during follow-up.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
- Received July 10, 2019.
- Accepted January 16, 2020.
- Copyright © 2020 by the American Society of Nephrology