Kerry Cooper

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

BACKGROUND AND OBJECTIVES Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a prospective, multicenter, phase 4, randomized, open-label study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH >450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH <300 pg/ml or a ≥30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken. RESULTS Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was -12.1% (-20.0% to -4.1%) in the cinacalcet arm and -7.0% (-14.9% to 0.8%) in the vitamin D analog arm, a difference of -5.0% (-15.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH≤300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction >30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P<0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm. CONCLUSIONS Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels.

Efficacy of cinacalcet with low-dose vitamin D in incident haemodialysis subjects with secondary hyperparathyroidism

BACKGROUND Treatment with cinacalcet improves the control of secondary hyperparathyroidism (SHPT) and the achievement of calcium and phosphorus targets. Most data come from subjects receiving cinacalcet after several years of dialysis treatment. We therefore compared the efficacy of treatment with cinacalcet and low doses of active vitamin D to flexible doses of active vitamin D alone for the management of SHPT in patients recently initiating haemodialysis. METHODS This open-label trial randomized subjects (n = 309) with parathyroid hormone (PTH) >300 pg/mL on dialysis for 3-12 months to either cinacalcet with low-dose active vitamin D, if prescribed (cinacalcet); or usual care without cinacalcet (control). Randomized subjects were stratified by PTH at screening (300-450, >450-600, >600 pg/mL) and by the use of active vitamin D at enrolment. Treatment duration was 12 months, with primary efficacy endpoint (mean PTH reduction ≥ 30% from baseline) assessed at 6 months. RESULTS The mean [standard deviation (SD)] haemodialysis vintage at enrolment was 7.2 (2.7) months; 53% of subjects were not receiving active vitamin D at enrolment. There was a significant difference in the achievement of the primary endpoint (≥ 30% PTH reduction at 6 months) between cinacalcet-treated subjects and controls in both the entire cohort (63 versus 38%; n = 304; P < 0.0001) and the subgroup of subjects not receiving active vitamin D at enrolment (70 versus 44%; n = 161; P < 0.01). Hypocalcaemia and gastrointestinal adverse events were more commonly observed in cinacalcet-treated subjects. CONCLUSIONS These results indicate that cinacalcet with low-dose active vitamin D, if prescribed, provides a more effective treatment approach than usual care without cinacalcet for SHPT in incident haemodialysis patients, even in relatively treatment-naive patients.

Effect of Cinacalcet and Vitamin D Analogs on Fibroblast Growth Factor-23 during the Treatment of Secondary Hyperparathyroidism

BACKGROUND AND OBJECTIVES Cinacalcet and vitamin D are often combined to treat secondary hyperparathyroidism (SHPT) in patients on dialysis. Independent effects on fibroblast growth factor-23 (FGF-23) concentrations in patients on hemodialysis administered cinacalcet or vitamin D analogs as monotherapies during treatment of SHPT are evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter, randomized, open-label study to compare the efficacy of cinacalcet versus traditional vitamin D therapy for management of secondary hyperparathyroidism among subjects undergoing hemodialysis (PARADIGM) was a prospective, phase 4, multicenter, randomized, open-label study conducted globally. Participants (n=312) were randomized 1:1 to cinacalcet (n=155) or vitamin D analog (n=157) for 52 weeks. Levels of FGF-23 were measured at baseline and weeks 20 and 52. The absolute and percentage changes from baseline in plasma FGF-23, parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and calcium-phosphorus product (Ca×P) were assessed. Correlations and logistic regression were used to explore relationships between changes in FGF-23 and changes in PTH, Ca, P, and Ca×P from baseline to week 52 by treatment arm. RESULTS Median (quartiles 1, 3) decrease in FGF-23 concentrations was observed in the cinacalcet arm (-40%; -63%, 16%) compared with median increase in the vitamin D analog arm (47%; 0%, 132%) at week 52 (P<0.001). Changes in FGF-23 in both arms were unrelated to changes in PTH (cinacalcet: r=0.17, P=0.11; vitamin D analog: r=-0.04, P=0.70). Changes in FGF-23 in the vitamin D analog but not the cinacalcet arm were correlated with changes in Ca (cinacalcet: r=0.11, P=0.30; vitamin D analog: r=0.32, P<0.01) and P (cinacalcet: r=0.19, P=0.07; vitamin D analog: r=0.49, P<0.001). Changes in FGF-23 were correlated with changes in Ca×P in both arms (cinacalcet: r=0.26, P=0.01; vitamin D analog: r=0.57, P<0.001). Independent of treatment arm, participants with reductions in P or Ca×P were significantly more likely to show reductions in FGF-23. CONCLUSIONS During treatment of SHPT, cinacalcet use was associated with a decrease in FGF-23 concentrations, whereas vitamin D analogs were associated with an increase. The divergent effects of these treatments on FGF-23 seem to be independent of modification of PTH. It is possible that effects of cinacalcet and vitamin D analogs on FGF-23 may be mediated indirectly by other effects on bone and mineral metabolism.

Facility Dialysate Calcium Practices and Clinical Outcomes Among Patients Receiving Hemodialysis: A Retrospective Observational Study.

BACKGROUND Some US dialysis facilities have reduced default dialysate calcium concentrations from 2.5 mEq/L to lower levels. There has been no rigorous systematic examination of the effects of such a reduction on clinical and biochemical outcomes. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS Medicare-eligible patients who received in-center hemodialysis at a large dialysis organization in January 2008 to December 2010. PREDICTOR Facility conversion from predominant use (≥75% patients) of 2.50-mEq/L dialysate calcium to predominant use of lower dialysate calcium concentrations versus maintenance of predominant use of 2.50-mEq/L dialysate calcium. OUTCOMES All-cause and cause-specific mortality and hospitalization, laboratory markers of metabolic bone disease, and drug utilization. MEASUREMENTS Hierarchical mixed linear and Poisson models were fit to compare pre- to postconversion differences in outcomes between converter and matched control facilities. Results, expressed as relative rate ratios (RRRs) and delta-delta (change in mean values), were estimated for early (months 0-2) and late (months 3-12) postconversion to allow for possible latent effects. RESULTS Facility conversion was associated with greater rates of hospitalization for heart failure exacerbation (late RRR, 1.27 [95% CI, 1.06-1.51]), hypocalcemia (early RRR, 1.19 [95% CI, 1.05-1.35]; late RRR, 1.39 [95% CI, 1.20-1.60]), and intradialytic hypotension (early RRR, 1.07 [95% CI, 1.02-1.11]; late RRR, 1.05 [95% CI, 1.01-1.10]), but no differences were observed for all-cause mortality or hospitalization rates. Facility conversion was also associated with comparative temporal decreases in serum calcium level, increases in serum phosphate and parathyroid hormone levels, and increases in use of phosphate binders, vitamin D, and calcimimetics. LIMITATIONS Possible residual confounding, generalizability beyond Medicare patients uncertain. CONCLUSIONS There are potential safety concerns associated with the default use of dialysate calcium concentrations < 2.50 mEq/L, as well as biochemical evidence of poorer disease control despite associated greater medication use. Individualization of dialysate calcium concentration rather than predominant use of dialysate calcium concentrations < 2.50 mEq/L should be considered.

Relationship between Reductions in Parathyroid Hormone and Serum Phosphorus during the Management of Secondary Hyperparathyroidism with Calcimimetics in Hemodialysis Patients

Background/Aim: The relationship between changes in plasma parathyroid hormone (PTH) and serum phosphorus levels during treatment with cinacalcet was evaluated in hemodialysis patients with secondary hyperparathyroidism (SHPT) receiving stable doses of vitamin D. Methods: Post hoc analysis of the relationship between PTH and phosphorus levels before and during treatment with cinacalcet in adult subjects on hemodialysis with inadequately controlled SHPT (PTH ≥300 pg/ml) included: (1) correlation of absolute changes from baseline in mean PTH and phosphorus at week 2 and during weeks 13–26; (2) phosphorus levels at baseline and absolute and percent change of phosphorus after cinacalcet administration stratified by baseline PTH level; (3) two regression analyses models were fitted that (a) adjusted for baseline lab values to quantify the relationship between changes in PTH and changes in phosphorus and (b) a multivariate regression analysis that adjusted for clinically relevant subject characteristics. Results: Serum phosphorus concentrations at baseline were incrementally greater by PTH stratum from lowest to highest. Reductions in PTH from baseline after 13–26 weeks of treatment with cinacalcet were associated with corresponding reductions in serum phosphorus. Two weeks after starting treatment with cinacalcet when doses of vitamin D analogues, phosphate binders, and cinacalcet remained unchanged, there was a statistically significant association (p < 0.0001) between the decreases from baseline in PTH and phosphorus. Conclusions: Reductions in PTH during cinacalcet therapy are associated with decreases in serum phosphorus that cannot be explained by changes in vitamin D or phosphate binder therapy, and may reflect diminished phosphorus release from bone.

Management of serum calcium reductions among patients on hemodialysis following cinacalcet initiation

Cinacalcet is indicated for treatment of secondary hyperparathyroidism in patients receiving hemodialysis. Cinacalcet reduces serum calcium concentrations by decreasing parathyroid hormone secretion, but the frequency and degree of calcium reduction following cinacalcet initiation, subsequent physician response, and ultimate calcium recovery in clinical practice are not well described.

Co-trending of parathyroid hormone and phosphate in patients receiving hemodialysis

AIM The objective of this study was to examine the time-varying relationship of chronic kidney disease-mineral bone disorder (CKD-MBD) related biochemical parameters (parathyroid hormone (PTH), calcium, phosphate) over a 12-month period. MATERIAL AND METHODS Using data from a large US provider of dialysis services from 2010 through 2012, we constructed a cohort of adult patients receiving in-center hemodialysis who had biochemical parameters measured at both baseline and 12 months of follow-up. We used descriptive statistics to assess the overall distributions of the biochemical parameters at both measurements, to examine how patients transitioned between categories for each biochemical parameter, and to evaluate how the biochemical parameters changed with respect to each other. RESULTS Among the 132,087 patients included in our analyses, the cross-sectional distributions for the combined categories of 150 - < 300 and 300 - < 600 pg/mL for PTH between the two measurements remained unchanged (67% of patients). For calcium and phosphate, the distributions across all categories also remained largely unchanged. Considering within-patient changes over time. however, a majority (74%) of patients who initially had a PTH < 150 pg/mL transitioned to a higher category, while a majority (56%) of patients who initially had a PTH > 600 pg/mL transitioned to a lower category. We observed that phosphate values on average directly trended with PTH values over the follow-up period. CONCLUSION We found that while calcium showed relatively little variation, parallel bidirectional variation in PTH and phosphate over time was quite common among adult patients receiving hemodialysis. Optimal control of phosphate is likely to be dependent not only on consistent adherence to dietary restrictions and phosphate binders, but may additionally rely on adequate and sustained control of PTH.

Geovariation in Fracture Risk among Patients Receiving Hemodialysis

BACKGROUND AND OBJECTIVES Fractures are a major source of morbidity and mortality in patients receiving dialysis. We sought to determine whether rates of fractures and tendon ruptures vary geographically. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from the US Renal Data System were used to create four yearly cohorts, 2007-2010, including all eligible prevalent patients on hemodialysis in the United States on January 1 of each year. A secondary analysis comprising patients in a large dialysis organization conducted over the same period permitted inclusion of patient-level markers of mineral metabolism. Patients were grouped into 10 regions designated by the Centers for Medicare and Medicaid Services and divided by latitude into one of three bands: south, <35°; middle, 35° to <40°; and north, ≥40°. Poisson regression was used to calculate unadjusted and adjusted region-level rate ratios for events. RESULTS Overall, 327,615 patients on hemodialysis were included. Mean (SD) age was 61.8 (15.0) years old, 52.7% were white, and 55.0% were men. During 716,962 person-years of follow-up, 44,014 fractures and tendon ruptures occurred, the latter being only 0.3% of overall events. Event rates ranged from 5.36 to 7.83 per 100 person-years, a 1.5-fold rate difference across regions. Unadjusted region-level rate ratios varied from 0.83 (95% confidence interval, 0.81 to 0.85) to 1.20 (95% confidence interval, 1.18 to 1.23), a 1.45-fold rate difference. After adjustment for a wide range of case mix variables, a 1.33-fold variation in rates remained. Rates were higher in north and middle bands than the south (north rate ratio, 1.18; 95% confidence interval, 1.13 to 1.23; middle rate ratio, 1.13; 95% confidence interval, 1.10 to 1.17). Latitude explained 11% of variation, independent of region. A complementary analysis of 87,013 patients from a large dialysis organization further adjusted for circulating mineral metabolic parameters and protein energy wasting yielded similar results. CONCLUSIONS Rates of fractures vary geographically in the United States dialysis population, even after adjustment for known patient characteristics. Latitude seems to contribute to this phenomenon, but additional analyses exploring whether other factors might influence variation are warranted.

Calcium-Mediated Parathyroid Hormone Suppression to Assess Progression of Secondary Hyperparathyroidism During Treatment Among Incident Dialysis Patients

CONTEXT Parathyroid gland function is affected adversely by tissue hyperplasia and gland enlargement in hyperparathyroidism. OBJECTIVE We examined the effects of 2 treatment strategies on the progression of secondary hyperparathyroidism using measurements of the nonsuppressible component of calcium-regulated PTH secretion as an index of parathyroid mass. DESIGN, SUBJECTS, AND INTERVENTION In this randomized, open-label study, subjects managed with hemodialysis for >3 but <12 months before entering the trial (mean, 7.2 months) who had baseline plasma PTH levels >300 pg/mL received cinacalcet and low-dose vitamin D sterols (Cin-D, n = 153) or larger, varying doses of calcitriol, or other vitamin D analogs (Flex-D, n = 151). Study drug doses were adjusted periodically based on PTH and serum total calcium determinations. MAIN OUTCOME MEASURES The exploratory endpoint was calcium-regulated PTH release, assessed using a standardized PTH suppression test before and after 52 weeks of treatment and 4 weeks after withdrawing treatment. PTH and serum total calcium were measured before hemodialysis using high-calcium (3.5 mEq/L or 1.75 mmol/L) dialysate and after 150 and 180 minutes. RESULTS Mean (95% confidence interval) nonsuppressible calcium-regulated PTH release at baseline did not differ between Cin-D, 33.4% (25.9%, 40.9%), and Flex-D, 28.1% (23.2%, 32.9%). Corresponding values after 52 weeks of treatment were 34.3% (29.7%, 38.9%) and 42.0% (32.7%, 51.3%), not significant, and did not change measurably in either group when reevaluated 4 weeks after treatments were withdrawn. CONCLUSION Disease progression over 12 months was not documented using a PTH suppression test in this population. Calcium-mediated PTH suppression was maintained fully, however, in Cin-D despite reductions in serum total calcium concentration, whereas values did not increase in Flex-D despite substantial increases in serum calcium.

Hemodialysis patients’ preferences for the management of secondary hyperparathyroidism

BackgroundPatient engagement and patient-centered care are critical in optimally managing patients with end-stage renal disease (ESRD). Understanding patient preferences is a key element of patient-centered care and shared decision making. The objective of this study was to elicit patients’ preferences for the treatment of secondary hyperparathyroidism (SHPT) associated with ESRD using a discrete-choice experiment survey.MethodsClinical literature, nephrologist input, patient-education resources, and a patient focus group informed development of the survey instrument, which was qualitatively pretested before its administration to a broader sample of patients. The National Kidney Foundation invited individuals in the United States with ESRD who were undergoing hemodialysis to participate in the survey. Respondents chose among three hypothetical SHPT treatment alternatives (two medical alternatives and surgery) in each of a series of questions, which were defined by attributes of efficacy (effect on laboratory values and symptoms), safety, tolerability, mode of administration, and cost. The survey instrument included a best-worst scaling exercise to quantify the relative bother of the individual attributes of surgery. Random-parameters logit models were used to evaluate the conditional relative importance of the attributes.ResultsA total of 200 patients with ESRD completed the survey. The treatment attributes that were most important to the respondents were whether a treatment was a medication or surgery and out-of-pocket cost. Patients had statistically significant preferences for efficacy attributes related to symptom management and laboratory values, but placed less importance on the attributes related to mode of administration and side effects. The most bothersome attribute of surgery was the risk of surgical mortality.ConclusionsPatients with ESRD and SHPT who are undergoing hemodialysis understand SHPT and have clear and measurable treatment preferences. These results may help inform clinicians about patients’ preferences regarding treatment options for a common complication of ESRD.