To determine whether the calcimimetic agent, cinecalcet, will control secondary hyperparathyroidism in hemodialysis patients more effectively than standard treatment (phosphate binding agents and/or vitamin D sterols)
Study design and study population:
Stable chronic hemodialysis patients, on standard therapy for CKD-MBD (oral dietary phosphate binding agents with/without vitamin D analogues) were eligible for inclusion if they had a stable serum (intact) PTH level of at least 31.8 pmol/L (300 pg/ml) Designed as 2 identical RCT’s conducted at 63 sites in N.America and 62 in Europe/Asia. Randomisation was stratified by disease severity; no more than 20% of the population could have serum PTH levels > 84.8 pmol/L (800 pg/ml). Standard therapy was continued with oral phosphate binders (no restrictions) and vitamin D analogues (dose could be adjusted according to evolving serum PTH levels). A total of 741 patients were enrolled out of a total of 1270 screened.
Intervention or observation
Patients were randomized to cinecalcet or placebo. Treatment phase lasted 26 weeks, with a 12 week dose titration (starting at 30 mg /day, to a maximum of 180 mg/day), followed by a 14 week efficacy assessment phase.
Primary and Secondary End-points
Primary: Proportion of patients with mean serum PTH < 26.5 pmol/L (250 pg/ml)
Secondary: Proportion of patients with 30% reduction in serum PTH below baseline. Percent change in serum PTH, calcium, phosphate, Ca x Phos product and bone-specific alkaline phosphatase (BSAP)
Statistical analysis: Cochran–Mantel–Haenszel tests were used to estimate the relative risk of the primary end point in the cinecalcet group, as compared with the placebo group, according to age, sex, race, duration of dialysis, base-line biochemical variables, presence or absence of diabetes, and use (or nonuse) of vitamin D sterols.
On average patients were 54-55 yrs. old, undergoing HD for 72 mon., and 1/3 were diabetic. 2/3 of the patients were receiving vitamin D sterols, and almost all continued with phosphate binders. Baseline serum PTH levels were similar in both groups (average 68 pmol/L)
Significantly larger numbers of patients reached the 10 end point after taking cinecalcet (43% vs 5%, p<0.001). Mean serum PTH decreased by >30% in significantly more patients taking cinecalcet ( 64% vs 11%, p< 0.001). There was little or no influence on the efficacy of cinecalcet as a function of the confounding variables listed above.
Patients receiving cinecalcet experienced modest reductions in serum calcium (6.8%), phosphate (8.4%), and Ca x Phos product (14.6%). Median reductions in BSAP were significantly greater in the cinecalcet group than in placebo (35% vs 4%). These changes were all significant (p<0.001)
Over 80% of the enrolled cohort completed the dose titration phase, with slightly fewer patients on cinecalcet (68%) completing the efficacy assessment phase than those on placebo (78%). Adverse events were the commonest cause for withdrawal (cinecalcet 15%, Placebo 7%). Clinically important side effects during cinecalcet therapy were nausea and vomiting, but rarely severe enough to stop treatment ( < 5% patients on cinecalcet vs <1% on placebo). Hypocalcemia ( <1.9 mmol/L) occurred in <5% patients on cinecalcet vs < 1% on Placebo.
This was a well conducted study, involving a large patient population, conducted as a randomized, placebo-controlled trial. Control of 20 hyperparathyroidism was impressive, given the severity of the disease at baseline (serum PTH averaged 68 pmol/L pre-treatment). Cinecalcet was well tolerated, although GI side effects are not trivial. The authors provided no data on final doses necessary to achieve the stated end points.
The efficacy assessment phase was relatively short (14 weeks). While there is no suggestion that a refractory state develops over this short duration, long term data are needed to confirm that. There is no information about patient-related outcomes. Some outcomes of particular importance include the ability of cinecalcet to preclude the need for parathyroidectomy, prevention or reversal of vascular calcification, reduction in vascular events associated with calcific atherosclerosis, improved mortality. Large long-term trials are underway to address some of these issues.
Cinecalcet is clearly a potent therapy for the suppression of secondary hyperparathyroidism. It has the particular advantage over the use of vitamin D analogues in that it does not predispose to hypercalcemia or increase GI absorption of calcium salts. However it has extremely limited formulary access due to its high cost (> $4,000 retail /yr. at an entry dose of 30 mg. /d). Unless ongoing trials evaluating patient-centered outcomes confirm more tangible benefits than biochemical remission of secondary hyperparathyroidism, it is unlikely to find widespread usage in dialysis populations.