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PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

ABSTRACT: Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ? 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR]?= 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.

SUBMITTER: Akizawa T

PROVIDER: S-EPMC4829837 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Akizawa Tadao T Kurita Noriaki N Mizobuchi Masahide M Fukagawa Masafumi M Fukagawa Masafumi M Onishi Yoshihiro Y Yamaguchi Takuhiro T Ellis Alan R AR Fukuma Shingo S Alan Brookhart M M Hasegawa Takeshi T Kurokawa Kiyoshi K Fukuhara Shunichi S

Scientific reports 20160413

Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relation ...[more]

PMID: 27071541

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Project description:BackgroundSecondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) leading high mortality and even long-term morbidity. SHPT is manifested by elevation of parathyroid hormone (PTH) and accurate determining the level of serum PTH is very essential for early diagnosis of SHPT secondary to CKD. It is very important to match the values obtained for intact parathormone (iPTH) and 1- 84 PTH with the minimized measurement bias.ObjectivesThe present study aimed to first determine the agreement value between the iPTH and 1- 84 PTH measures in patients with hyperparathyroidism secondary to endstage renal disease under chronic hemodialysis. Then, we attempted to determine the best cutoff values for these two measurements for detecting SHPT in such patients.Patients and methodsThis cross-sectional study was conducted on hemodialysis patients. The value of study biomarkers including iPTH and 1- 84 PTH was assessed.ResultsA strong positive association was revealed between the two indicators of iPTH and 1-84 PTH (r = 0.800, P < 0.001). The linear association between these two parameters is independent to baseline characteristics including gender, age, body mass index, and medical history. Among all biochemical elements, the value of 1-84 PTH was only associated with serum calcium level negatively (r = -0.267, P = 0.027) and alkaline phosphatase positively (r = 0.359, P = 0.003). Considering iPTH as the reference and according to the area under the ROC curve (AUC), 1-84 PTH had high value to predict hyperparathyroidism (AUC = 0.926, P < 0.001). The best cutoff point for 1-84 PTH to discriminate hyperparathyroidism from normal condition was 60 yielding a sensitivity of 92.3% and a specificity of 79.1%. Among other baseline laboratory parameters, only alkaline phosphatase had an acceptable value for diagnosing hyperparathyroidism (AUC = 0.731, P = 0.001).ConclusionsThe measurement of both iPTH and 1-84 PTH is valuable for predicting hyperparathyroidism secondary to CKD, but according to lower cost and comparableeffectiveness of iPTH measurement, this assay may be comparable to 1-84 PTH to predict this consequence.

Project description:IntroductionCalcimimetics improve parameters of secondary hyperparathyroidism (sHPT) but are mostly initiated when patients have severe disease, potentially limiting effectiveness. We evaluated the effects of etelcalcetide on lowering intact parathyroid hormone, calcium, and phosphate at different disease severity levels.MethodsThis analysis examined data from 2 parallel, phase 3, randomized, placebo-controlled, 26-week trials conducted in 1023 adult (≥18 years old) patients with sHPT on maintenance hemodialysis. Etelcalcetide effects by baseline intact parathyroid hormone stratum (<600, 600-1000, and >1000 ng/l) on mean percentage change in intact parathyroid hormone; changes in calcium and phosphate; and achieving serum intact parathyroid hormone ≤300 ng/l, phosphate <1.78 mmol/l, and both combined, were assessed.ResultsEtelcalcetide reduced serum intact parathyroid hormone by a similar percentage across baseline strata. A similar proportion achieved >30% intact parathyroid hormone reduction across strata for the etelcalcetide arms. Parathyroid hormone increased modestly in each placebo-group stratum, most prominently in the lowest stratum. Serum calcium and phosphate concentrations decreased across strata in etelcalcetide-treated patients, with the most pronounced reductions in patients with highest baseline parathyroid hormone. However, the proportion of patients achieving parathyroid hormone, phosphate, and both targets was highest in the lowest baseline parathyroid hormone stratum, where etelcalcetide dose requirements were lowest. Etelcalcetide dose requirement was lowest among patients in the lowest intact parathyroid hormone stratum.ConclusionEtelcalcetide effectively lowered serum intact parathyroid hormone, calcium, and phosphate, irrespective of the severity of secondary hyperparathyroidism. The ability to achieve target goals was greatest, and dose requirement smallest, when etelcalcetide was initiated among patients with the lowest level of disease severity.

Project description:BackgroundCalcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials.MethodsThis analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed.ResultsOverall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients.ConclusionsThis integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.

Dataset Information

PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Publications

PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

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