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Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol.

ABSTRACT: BACKGROUND: Secondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D.In Denmark alfacalcidol is the primary choice of vitamin D analog.A new vitamin D analog, paricalcitol, may be less prone to induce hypercalcemia and hyperphosphatemia.However, a randomised controlled clinical study comparing alfacalcidol and paricalcitol has never been performed.The primary objective of this study is to compare alfacalcidol and paricalcitol. We evaluate the suppression of the secondary hyperparathyroidism and the tendency towards hyperphosphatemia and hypercalcemia. METHODS/DESIGN: This is an investigator-initiated cross-over study. Nine Danish haemodialysis units will recruit 117 patients with end stage renal failure on maintenance haemodialysis therapy.Patients are randomised into two treatment arms. After a wash out period of 6 weeks they receive increasing doses of alfacalcidol or paricalcitol for a period of 16 weeks and after a further wash out period of 6 weeks they receive the contrary treatment (paricalcitol or alfacalcidol) for 16 weeks. DISCUSSION: Hyperparathyroidism, hypercalcemia and hyperphosphatemia are associated with increased cardiovascular mortality in patients with chronic kidney disease.If there is any difference in the ability of these two vitamin D analogs to decrease the secondary hyperparathyroidism without causing hypercalcemia and hyperphosphatemia, there may also be a difference in the risk of cardiovascular mortality depending on which vitamin D analog that are used. This has potential major importance for this group of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00469599.

SUBMITTER: Hansen D

PROVIDER: S-EPMC2760547 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol.

Hansen Ditte D Brandi Lisbet L Rasmussen Knud K

BMC nephrology 20090924

<h4>Background</h4>Secondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D ...[more]

PMID: 19778452

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Project description:Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.

Project description:ImportancePatients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels.ObjectiveTo determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis.Design, setting, and participantsRandomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015.InterventionsTreatment with 0.5 μg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481).Main outcomes and measuresThe primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death.ResultsAmong 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events.Conclusions and relevanceAmong patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these.Trial registrationUMIN-CTR Identifier: UMIN000001194.

Project description:BackgroundThe IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism] study compared the effectiveness of paricalcitol and cinacalcet in the management of secondary hyperparathyroidism in haemodialysis patients but did not report the costs or cost effectiveness of these treatments.AimThe aim of this study was to compare the cost effectiveness of a paricalcitol-based regimen versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients from a US payer perspective, using a 1-year time horizon.MethodsThis was a post hoc cost-effectiveness analysis of data collected for US patients enrolled in the IMPACT SHPT study-a 28-week, randomized, open-label, phase 4, multinational study (ClinicalTrials.gov identifier: NCT00977080). Patients eligible for the IMPACT SHPT study were aged≥18 years with stage 5 chronic kidney disease, had been receiving maintenance haemodialysis three times weekly for at least 3 months before screening and were to continue haemodialysis during the study. Only US patients who reached the evaluation period (weeks 21-28) were included in this secondary analysis. US subjects in the IMPACT SHPT study were randomly assigned to receive intravenous paricalcitol, or oral cinacalcet plus fixed-dose intravenous doxercalciferol, for 28 weeks. Patients in the paricalcitol group could also receive supplemental cinacalcet for hypercalcaemia. The primary effectiveness endpoint in the IMPACT SHPT study was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) level of 150-300 pg/mL during the evaluation period. In this secondary analysis, we estimated the incremental cost-effectiveness ratio (ICER), comparing paricalcitol-treated patients with cinacalcet-treated patients on the basis of this primary endpoint and several secondary endpoints. Costs were estimated by examining the dosage of the study drug (paricalcitol or cinacalcet) and phosphate binders used by each participant during the trial. Nonparametric bootstrap analysis was used to examine the accuracy of the ICER point estimates.ResultsThe percentages of patients achieving the treatment goal of a mean iPTH level between 150-300 pg/mL during weeks 21-28 of therapy were 56.9% in the paricalcitol group and 34.0% in the cinacalcet group (a difference of 23%, p=0.0235). Paricalcitol was also more effective for each of the secondary endpoints. When annualized, the total drug costs were US$10,153 in the paricalcitol group and US$15,967 in the cinacalcet group, a difference of US$5,814 (57.3%, p=0.0053). Because the paricalcitol-based treatment was less expensive and more effective, it was 'dominant', compared with cinacalcet, in this cost-effectiveness analyses. In our bootstrap analysis, 99.1% of bootstrap replicates for the ICER of the primary endpoint fell within the lower right quadrant of the cost-effectiveness plane-where paricalcitol is considered dominant. For all of the other endpoints, paricalcitol was dominant in 100% of replicates.ConclusionOn the basis of dosing and effectiveness data from US patients in the IMPACT SHPT study, we found that a regimen of intravenous paricalcitol was more cost effective than cinacalcet plus low-dose vitamin D in the management of iPTH in patients with SHPT requiring haemodialysis.

Project description:Background and objectivesCalcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%-60%.Design, setting, participants, & measurementsPatients with stages 3-4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 μg/d of calcitriol or 1 μg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%-60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups.ResultsForty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (-52% with paricalcitol and -46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3-0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups.ConclusionsThese results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3-4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.

Project description:BackgroundSecondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control.MethodsThis is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months.ResultsThere was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses.ConclusionsWith a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.

Project description:The management of hyperparathyroidism in hemodialysis patients involves the administration of phosphate binders, vitamin D receptor activators, and calcimimetics. Intravenous paricalcitol has been preferred over oral calcitriol as it may cause less hypercalcemia and hyperphosphatemia. However, there is little data looking at the efficacy and tolerability of oral calcitriol in the calcimimetic era particularly in a real practice-based experience. The University of California, Irvine free-standing dialysis center converted from routine intravenous paricalcitol to oral calcitriol due to pharmacy purchasing preferences. We report the efficacy, safety, and cost of such a change.Ninety-three preconversion intravenous paricalcitol and 91 postconversion oral calcitriol.Conversion to in-center, pulse, oral calcitriol (0.25 mcg = 1 mcg paricalcitol) 3 times a week from intravenous paricalcitol. Additional dose adjustments were made by the nephrologists based on clinical indications.Five-month average serum calcium, phosphorous, and intact parathyroid hormone levels and cardiovascular events pretransition and posttransition.There were 93 patients on intravenous paricalcitol between April 2013 and August 2013, of which 74 converted to oral calcitriol and were included in the postconversion group evaluated between October 2013 and February 2014. An additional 17 new patients had initiated calcitriol such that 91 patients were on oral therapy in the postconversion period. Sevelamer use increased from 41 (44.1%) patients preconversion to 48 (52.7%) postconversion, whereas calcium acetate use significantly dropped from 62 (66.7%) to 46 (50.5%) (P = .026). Cinacalcet use dropped slightly from 37 (39.7%) patients preconversion to 35 (38.4%) postconversion. Average serum calcium, phosphorus, and intact parathyroid hormone levels remained unchanged after conversion. Percent of values within Kidney Disease Outcome Quality Initiative guidelines were similarly maintained. Estimated vitamin D cost savings were $564 per person/year. No increase in the incidence of cardiovascular events was observed.We conclude that in-center distributed pulse oral calcitriol may be an effective, safe, and economical treatment option for the management of hyperparathyroidism in hemodialysis patients.

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Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol.

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Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol.

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