Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol-treated patients in real-world clinical settings

Deborah G. Dobrez1,2, Angelo Mathes3, Michael Amdahl4, Steven E. Marx3, Joel Z. Melnick5 and Stuart M. Sprague2,6

1Center for Outcomes Research and Education, Evanston Northwestern Healthcare, Evanston, IL, 2Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 3Center for Pharmaceutical Appraisal and Outcomes, 4Department of Statistics and 5Global Renal Project Team, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL and 6Department of Nephrology and Hypertension, Evanston Northwestern Healthcare, Evanston, IL, USA

Correspondence and offprint requests to: Deborah G. Dobrez, PhD, Research Assistant Professor, Northwestern University, 339 East Chicago Avenue, Chicago, IL 60611, USA. Email: d-dobrez{at}northwestern.edu



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Abnormalities of serum calcium, phosphorous and intact parathyroid hormone (PTH) are associated with morbidity and mortality in haemodialysis patients. Pharmacologic parenteral vitamin D administration is used to correct these abnormalities; however, the relationship between vitamin D therapies and hospitalizations has never been addressed.

Methods. Healthcare data from January 1999 to November 2001 were analysed for 11 443 adult haemodialysis patients who received at least 10 doses of vitamin D therapy. Multivariate models were used to evaluate the effects of vitamin D therapy on: (i) total number of hospitalizations, (ii) total number of hospital days and (iii) risk of first hospitalization after initiation of vitamin D therapy.

Results. When compared with the calcitriol group, the paricalcitol group had a lower risk of first all-cause hospitalization (14% less likely, P<0.0001), fewer hospitalizations per year (0.642 fewer, P<0.001) and fewer hospital days per year (6.84 fewer, P<0.001). In the paricalcitol and calcitriol groups, respectively, 5.6 and 41.3% patients switched to another vitamin D compound. For those patients who started and remained on the same vitamin D product, paricalcitol-treated patients experienced 0.846 fewer hospitalizations per year and 9.17 fewer hospital days per year, P<0.001 for both. The paricalcitol group also had a lower risk of first PTH-related hospitalizations, fewer PTH-related annual hospitalizations and fewer days per year.

Conclusion. Paricalcitol-treated patients experienced fewer hospitalizations and hospital days per year when compared with calcitriol-treated patients. Initiating vitamin D therapy with paricalcitol may result in overall savings of ~$7600–11 000 per patient per year. A randomized, controlled, blinded study would be valuable in confirming and understanding these results.

Keywords: costs; haemodialysis; hospitalizations; hyperparathyroidism; multivariate; outcomes; vitamin D



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Secondary hyperparathyroidism affects at least half of the approximately 320 000 haemodialysis patients in the US who suffer from stage-V chronic kidney disease (CKD) (also known as end-stage renal disease or end stage kidney disease) [1,2]. Hyperparathyroidism is characterized by abnormally elevated serum concentrations of intact parathyroid hormone (PTH), and abnormalities of serum calcium, phosphorous and vitamin D concentrations. Inadequate treatment of hyperparathyroidism has been associated with the following conditions: skeletal abnormalities (renal osteodystrophy) [35], cardiovascular complications [6], infections and immunoregulatory dysfunction [710], foot and extremity complications [11], and anaemia. Patients on haemodialysis are at increased risk for fracture (including hip fracture) and calcific uraemic arteriolopathy (calciphylaxis), which result in significant morbidity (including hospitalization) and mortality [1215]. Treatment goals include decreasing PTH concentrations, and normalizing calcium and phosphate levels through dietary and drug therapies (such as calcium supplements, phosphate-binders and vitamin D compounds).

The relationship between PTH levels and morbidity has been examined in previous studies with contradictory results. Coco et al. reported associations between low PTH levels (<195 pg/ml) and increased risk of hospitalization due to hip fracture in 1272 dialysis patients based on chart review; however, data on other hospitalizations were unavailable [4]. In contrast, Stehman-Breen et al., using data from the US Renal Data System (USRDS) database, reported no association between baseline PTH concentrations and risk of hip fracture in 4952 haemodialysis patients [12]. Ganesh et al., using data from the USRDS database, determined that high baseline PTH (>495 pg/ml) was associated with sudden cardiac death; however, the impact on hospitalizations was not measured [15]. Although Tsuchihashi et al. reported a significant relationship between low PTH and cardiovascular complications in 48 patients, the data were analysed using logistic regression, which is better suited to large sample sizes [6]. Thus, earlier control of PTH may be an important factor associated with morbidity. Recently, paricalcitol has been shown to control PTH significantly sooner than calcitriol in haemodialysis patients [16].

To date, no observational study has measured the relationship between PTH levels and all-cause hospitalizations, and between PTH levels and hyperparathyroidism-related hospitalizations, in a comprehensive fashion. Furthermore, the relationship between available parenteral vitamin D therapies [in the US: calcitriol (Calcijex®, Abbott Laboratories Inc., Abbott Park, IL), paricalcitol (Zemplar®, Abbott Laboratories Inc., Abbott Park, IL) and doxercalciferol (Hectorol®, Bone Care International, Madison, WI] and hospitalizations has never been examined. The relationship between these treatments and hospitalizations (as opposed to the relationship between PTH and hospitalizations) is of great importance to the clinician who must choose among vitamin D treatments.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
Patient data were retrieved from the electronic medical record of a large, national, dialysis provider for the 35-month period from January 1, 1999 to November 30, 2001; patients who began parenteral vitamin D therapy at any time during that time period were included. To exclude paediatric patients and those patients who were not receiving chronic haemodialysis or chronic vitamin D therapy, the protocol specified the following inclusion criteria: new-to-dialysis CKD patients, at least 18 years of age, a minimum of 60 days of haemodialysis and a minimum of 10 intravenous (i.v.) vitamin D injections with either paricalcitol, calcitriol or doxercalciferol. Patients who received haemodialysis at a non-affiliated facility for >2 weeks were excluded.

Baseline data were collected and included: age; gender; race; Centers for Medicare and Medicaid Services (CMS) region of residence; co-morbid conditions (including diabetic status) categorized by International Classification of Disease Revision 9 (ICD-9) Code and grouped by body system; laboratory information; the estimated number of days of haemodialysis prior to initial vitamin D use; previous use of erythropoietin, iron supplements and antibiotics; and changes in vascular access. Intact PTH was measured using Nichols Advantage® Tests (Nichols Institute Diagnostics, CA).

Information regarding documented absences from haemodialysis for hospitalization (including the date of the absence, the discharge diagnosis and the date the patient returned to the dialysis clinic) was obtained for each patient. All individual patient data were used unless one of the following events occurred: dialysis modality changed to peritoneal dialysis, kidney transplant or death. If any of these events occurred, data utilization was discontinued from that point forward.

Outcome measures
Three primary outcomes of interest were specified a priori: (i) total number of all-cause hospital admissions during the observational period, (ii) total number of days for all-cause hospitalization during the observational period and (iii) time to (or risk of, in the case of the multivariate analyses) the first hospitalization after initiation of vitamin D therapy.

Hospitalizations were identified by documented absences from the dialysis clinic for hospitalization. Absences associated with changes in access were excluded. The number of days for each hospitalization was calculated as the number of days between the first documented absence and the return to the dialysis centre, plus 1 day (because time of admission and discharge information were not available).

Because each patient's data were evaluated from the initiation of vitamin D therapy until either a terminal study event occurred or until the end of the study (rather than for a specified length of time for all patients), a post-hoc decision was made to ‘time-standardize’ two of the three hospitalization outcomes to adjust for differing observational period lengths. The total number of hospitalizations and hospital days were divided by the time in years that data for the patient were observed in the database, thus normalizing each patient's cumulative use of hospital admissions and hospitalization days by years of on-treatment observation.

Hospitalizations related to hyperparathyroidism or vitamin D use were classified a priori into the following groups based upon ICD-9 codes: infections, neoplasms, anaemia, cardiovascular, non-infectious inflammation, neuropathies, bone and connective tissue disorder, fractures, lipid disorder, vitamin D deficiency, access-site complications, calciphylaxis and crystalopathies. Because the goal of vitamin D treatment is to manage hyperparathyroidism, it is likely that the choice of vitamin D treatment will have a more significant impact upon hyperparathyroidism-related hospitalizations than on hospitalizations for other causes.

Statistical methods
Descriptive summary statistics were used to characterize the relationships between initial vitamin D therapy and hospitalizations. Mean and median values were calculated for continuous variables, and percentages were calculated for categorical variables. Similarly, descriptive summary statistics and univariate statistical tests examined the differences in baseline characteristics between initial vitamin D treatment groups.

Two multivariate models to control for differences in baseline characteristics were specified a priori to examine the effect of vitamin D treatment choice (paricalcitol relative to calcitriol) on the dependent variable. Ordinary Least Squares (OLS) regressions were used for time-standardized total number of all-cause hospital admissions (rate of hospitalization) and for time-standardized total number of all-cause hospital days (rate of hospital days). The risk of first hospitalization (any-cause) was evaluated with Cox Proportional Hazards regression models.

The multivariate models were repeated in post-hoc analyses for time-standardized total number of PTH-related hospital admissions, total number of PTH-related hospital days, and risk of first PTH-related hospitalization (three additional models). Each multivariate model was also repeated for the five most frequent subclassifications of PTH-related complications (15 additional models).

Finally, post-hoc analyses (OLS regressions) were conducted for time-standardized total number of all-cause hospital admissions and total number of all-cause hospital days in the subset of patients who remained continuously on initial vitamin D therapy (patients who did not change to another vitamin D therapy).



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient population and treatment groups
A total of 25 345 haemodialysis patients, from a pool of 47 832 patients, met the study selection criteria. Fifty per cent of the eligible patients were then selected randomly. The number of patients was further reduced by excluding patients who received doxercalciferol, as there were too few (n = 50) to support a complete analysis, and by eliminating patients with incomplete data. The final population of 11 443 consisted of 4611 paricalcitol patients and 6832 calcitriol patients. A total of 94.4% of patients, who started on paricalcitol, remained on paricalcitol, while only 58.7% of patients who started on calcitriol, remained on calcitriol during the observational period.

Baseline characteristics
Paricalcitol patients began vitamin D therapy later than calcitriol patients during the course of haemodialysis, and experienced a significantly higher rate of co-morbid conditions at baseline than calcitriol patients. There were significant differences in ethnicity between patients starting paricalcitol or calcitriol. Paricalcitol patients were younger than calcitriol patients and were more likely to be female. There also were significant CMS regional differences (data not shown) between vitamin D groups, with paricalcitol use highest in the south (CMS Region IV). Baseline characteristics for patients who started vitamin D therapy with either paricalcitol or calcitriol are presented in Table 1.


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Table 1. Descriptive baseline statistics (n = 11 443)

 
A higher proportion of paricalcitol patients, as compared with calcitriol patients, had abnormally high baseline intact PTH and elevated baseline serum phosphorous concentrations. Conversely, paricalcitol patients were less likely to have low baseline serum calcium levels than calcitriol patients, while calcitriol patients were more likely to have low baseline serum albumin concentrations. Mean baseline serum PTH, calcium, phosphorus and alkaline phosphatase concentrations were 504 and 424 pg/ml, 8.6 and 8.4 mg/dl, 5.4 and 5.2 mg/dl and 123 and 123 U/l for paricalcitol and calcitriol patients, respectively.

Hospitalization outcomes results—descriptive
For all-cause hospitalizations, patients who started on paricalcitol had fewer admissions per year and shorter hospital lengths of stay per year than calcitriol patients. Simple descriptive statistics for hospital use (for patients who started vitamin D therapy with either paricalcitol or calcitriol) are presented in Table 2. Fewer paricalcitol patients required hospitalizations for PTH-related causes, infections, cardiovascular events, non-infectious inflammations and access-site complications than calcitriol patients (Figure 1). There were too few hospitalizations resulting from neoplasms, anaemia, neuropathies, bone and connective tissue disorder, lipid disorder, vitamin D deficiency, calciphylaxis, fractures or crystalopathies to support analysis.


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Table 2. Hospitalization outcomes: descriptive results (n = 11 443)

 


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Fig. 1. Descriptive results examining percentage of patients starting calcitriol (shaded bars) or paricalcitol (black bars) who were hospitalized at least once during the cohort (n = 11 443). *HTN, hypertension; PTH, intact PTH.

 
Hospitalization outcomes results—multivariate
In the intent-to-treat analysis, patients who started vitamin D therapy on paricalcitol had 6.84 fewer hospital days per year and 0.642 fewer hospital admissions per year (P<0.0001) than calcitriol patients. The results of the multivariate analyses conducted for the primary outcomes of interest are presented in Table 3. In an analysis of the subset of patients with monotherapy, patients who remained on paricalcitol had 9.17 fewer all-cause hospital days per year and 0.846 fewer all-cause hospitalizations per year, compared with patients who remained on calcitriol (Figure 2).


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Table 3. Impact on hospitalizations: OLS models (n = 11 443)

 


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Fig. 2. OLS models measuring the impact on all-cause hospitalizations in a subset of paricalcitol patients who remained exclusively on the initial vitamin D therapy (shaded square) compared with the intent-to-treat population (black square). Negative coefficients reflect fewer hospitalizations and hospital days for paricalcitol compared with calcitriol in both intent-to-treat and monotherapy groups. P<0.0001 for all (n = 11 443).

 
An intent-to-treat Cox Proportional Hazard regression model was used to assess the risk of first hospitalization. Patients who started on paricalcitol, relative to patients who started therapy on calcitriol, were 14% less likely to be hospitalized (Hazard Ratio = 0.863, P<0.0001).

The intent-to-treat effects of vitamin D treatment on the risk of first hospitalization, number of hospital admissions per year, and number of hospital days per year, and the results of 18 additional models that explored the effect of vitamin D treatment on hyperparathyroidism-related hospitalizations outcomes are presented in Table 4. The paricalcitol group, compared with the calcitriol group, had lower risks of first all-cause hospitalization and first hospitalization due to hyperparathyroidism-related complications, fewer all-cause hospitalizations per year, fewer hospitalizations due to hyperparathyroidism-related complications, fewer all-cause hospital days per year and fewer hospital days due to hyperparathyroidism-related complications.


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Table 4. All-cause and hyperparathyroidism-related hospitalizations: intent-to-treat effects of paricalcitol relative to calcitriol (n = 11 443)

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This retrospective study investigated health outcomes in a large, geographically diverse population of new-to-dialysis, stage-V CKD patients treated with haemodialysis and at least 10 i.v. administrations of vitamin D compounds. It was designed to examine the effects of vitamin D therapy, as well as numerous clinical and sociodemographic variables on various outcomes of interest. Three important outcomes were specified a priori: (i) total number of hospital admissions, (ii) total number of hospital days and (iii) time to (or risk of, in the case of the multivariate analyses) first hospitalization after initiation of vitamin D therapy.

Analyses documented clearly that statistically significant and clinically relevant differences related to clinical history, baseline laboratory values, geographic characteristics and co-morbid conditions existed between paricalcitol and calcitriol populations. The differences observed in baseline characteristics emphasized the need for multivariate statistical analyses, including controlling for confounding variables, to evaluate the impact of paricalcitol use on patient outcomes. Multivariate models were used to obtain more precise estimates of the effects of vitamin D therapy on hospitalizations, and demonstrated that paricalcitol patients experienced 0.642 fewer hospital admissions per year, 6.84 fewer hospital days per year, and a 14% lower risk of first hospitalization than calcitriol patients.

In addition, the multivariate models contained a time-in-study variable to account for varying lengths of observational periods among patients. Hospitalization outcomes would depend on duration of therapy. Patients who began therapy with calcitriol, the older vitamin D compound, were likely to have been on therapy longer. Thus, these patients would have been in the database longer and would have had the opportunity to experience a greater number of hospitalizations. The time-in-study variable was highly significant (P<0.003) and allowed for a less biased (removing time biases) estimate of the effect of paricalcitol relative to calcitriol on hospitalizations. No additional variables were created to assess the effect of time of entry, since hospitalization rates and lengths had not changed during observation period.

Because this was a retrospective study using real-world clinical data, not all patients remained on the same vitamin D treatment throughout the observational period. The paricalcitol group was relatively homogeneous with respect to vitamin D treatment; 94.4% started and remained on paricalcitol, while only 58.7% of the calcitriol group remained on calcitriol. All a priori analyses were conducted on an intent-to-treat basis, where treatment group assignment was based on initial vitamin D therapy. The intent-to-treat analyses demonstrated that initiating treatment with paricalcitol resulted in fewer hospitalizations, for each measure, when compared with initiating treatment with calcitriol. Additional analyses, in an attempt to remove switching biases, confirmed intent-to-treat results and demonstrated that patients who started and remained on paricalcitol had better hospitalization outcomes when compared with patients who started and remained on calcitriol.

These findings are consistent with recently published data on improved survival associated with vitamin D therapy in haemodialysis patients [17]. While subjects who switched between vitamin D therapies were removed from that study's analysis, paricalcitol therapy associated with significantly improved survival compared with calcitriol therapy. Of interest and similar to the morbidity benefit in our study, the survival benefit of paricalcitol appeared independent of serum levels of PTH, calcium and phosphorus.

Analyses were conducted to estimate the effects of initial vitamin D drug choice on hyperparathyroidism-related hospitalizations. The results of these analyses were consistent with the results demonstrated by the all-cause hospitalization models but less in magnitude. These findings suggest that vitamin D may play a beneficial role in preventing hospitalizations independent of its effect on hyperparathyroidism.

The financial implications of fewer hospitalizations are considerable. Using 2001 Medicare reimbursement data, the average reimbursement for a hospitalization for a dialysis patient may be estimated as follows [18,19]: DRG #478, other vascular procedure with complications, $9566.53; DRG #479, other vascular procedure without complications, $5873.66; average yearly reimbursement for a hospitalization, $7720.10; DRG #478, length of stay (indemnity plans), 6.95 days; DRG #479, length of stay (managed-care plans), 7.00 days; average yearly days of hospitalization, 6.95 days (DRG, diagnosis-related group).

Applying these estimates ($7720 divided by 6.95 days, or $1111 per day) to the results of this study (6.84 fewer hospital days favouring patients who started on paricalcitol) yields a cost savings of $7599 per patient per year ($1111 x 6.84) for each patient who started on paricalcitol as opposed to those who started on calcitriol. Other researchers have estimated the average cost (for all patients, not limited to dialysis patients) to be $1615 per day of hospitalization, which equals a hospital cost savings of $11 046 per patient per year [20]. Based on this study's findings and reimbursement assumptions, the potential cost savings from reduced hospitalization days of initiating vitamin D therapy with paricalcitol may range from ~$7600 to 11 000 per patient per year.

Analyses of drug treatment outcomes in retrospective studies are subject to selection bias in the assignment of drug treatment to patients when treatment assignment is in part a function of the patients’ expected outcomes. The analysis models used in this study control for multiple severity indicators (including PTH level) and co-morbidities that were hypothesized to affect hospitalization rates directly, or to affect both hospitalization rates and treatment choice. Models of drug choice conducted with the same patient sample demonstrated the high predictive value of these control variables in explaining drug choice. Patients on paricalcitol started haemodialysis with more co-morbid conditions and higher PTH levels, suggesting that sample selection is likely to bias results against paricalcitol, so that the study results can be interpreted as conservative. In addition, the fact that the calcitriol group was far more likely to switch vitamin D treatment than the paricalcitol group, suggests that differences in hospitalizations between the two groups may be attributable to either a beneficial effect of paricalcitol on hospitalization outcomes or an unobserved variable associated with initial drug choice. However, the results suggest the former because the negative impact on hospitalizations for patients who started and stayed on calcitriol is greater than those in the calcitriol intent-to-treat group. A prospective randomized trial is needed to confirm in a controlled setting the impact of selected vitamin D treatment on hospitalizations.

In summary, a large number of patients who started on calcitriol tended to change therapy. Paricalcitol-treated patients experienced improved hospitalization outcomes, compared with calcitriol-treated patients, in a real-world clinical setting. Hospitalization-related costs may therefore be substantially lower for paricalcitol-treated patients.



   Acknowledgments
 
We gratefully acknowledge Jeff McCombs PhD, Leonid Sokolski PharmD (PhD Candidate), Lei Chen MD (PhD Candidate), Jinhee Park PharmD (PhD Candidate) for their statistical and health economics support in this study. This research was funded by Abbott Laboratories.

Conflict of interest statement. The study was sponsored by Abbott Laboratories. Mr Amdahl, Dr Mathes, Dr Marx and Dr Melnick are employees of Abbott Laboratories. Dr Dobrez and Dr Sprague were paid consultancy fees by Abbott Laboratories.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 25. 6.03
Accepted in revised form: 17.12.03