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Effects of the Calcimimetic Cinacalcet Hcl on Cardiovascular Disease, Fracture, and Health-Related Quality of Life in Secondary Hyperparathyroidism

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Effects of the Calcimimetic Cinacalcet Hcl on Cardiovascular Disease, Fracture, and Health-Related Quality of Life in Secondary Hyperparathyroidism Kidney International, Vol. 68 (2005), pp. 1793–1800 Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism JOHN CUNNINGHAM,MARK DANESE,KURT OLSON,PRESTON KLASSEN, and GLENN M. CHERTOW University College London, The Middlesex Hospital, London, UK; Outcomes Insights, Inc., Newbury Park, California; Amgen, Inc., Thousand Oaks, California; and Department of Medicine, University of California, San Francisco, California Effects of the calcimimetic cinacalcet HCl on cardiovascular tion and diminished pain. These data suggest that, in addition disease, fracture, and health-related quality of life in secondary to its effects on PTH and mineral metabolism, cinacalcet had hyperparathyroidism. favorable effects on important clinical outcomes. Background. Secondary hyperparathyroidism (HPT) and ab- normal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the Secondary hyperparathyroidism (HPT) is a frequent calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concen- component of the natural progression of chronic kidney trations in patients with end-stage renal disease (ESRD) and disease (CKD), typically developing when the glomeru- secondary HPT. lar filtration rate (GFR) drops below approximately Methods. We undertook a combined analysis of safety data 80 mL/min/1.73m2 for ≥3 months [1]. Secondary HPT (parathyroidectomy, fracture, hospitalizations, and mortality) is an adaptive response to CKD and arises from dis- from 4 similarly designed randomized, double-blind, placebo- controlled clinical trials enrolling 1184 subjects (697 cinacalcet, ruptions in the homeostatic control of serum calcium, 487 control) with ESRD and uncontrolled secondary HPT (in- serum phosphorus, and vitamin D, which are associated tact PTH ≥300 pg/mL). Cinacalcet or placebo was administered with CKD. Characteristic skeletal features of secondary to subjects receiving standard care for hyperphosphatemia and HPT include increased bone turnover with abnormally secondary HPT (phosphate binders and vitamin D). Relative high rates of bone resorption, often accompanied by risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. bone pain and fractures [2–6]. Extraskeletal manifesta- Health-related quality-of-life (HRQOL) data were obtained tions of secondary HPT include vascular calcification, from the Medical Outcomes Study Short Form-36 (SF-36), and hypertension, anemia with erythropoietin resistance, pru- the Cognitive Functioning scale from the Kidney Disease Qual- ritus, and sexual dysfunction [7–14]. Conventional ther- ity of Life instrument (KDQOL-CF). apy for secondary HPT can contribute to hypercalcemia Results. Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI and hyperphosphatemia [15–17], laboratory abnormali- 0.01–0.55), fracture (RR 0.46, 95% CI 0.22–0.95), and cardio- ties associated with mortality in end-stage renal disease vascular hospitalization (RR 0.61, 95% CI 0.43–0.86) compared (ESRD) [18–21]. We have recently demonstrated higher with placebo. Changes in HRQOL favored cinacalcet, with sig- risks of cardiovascular disease and fracture associated nificant changes observed for the SF-36 Physical Component with hyperphosphatemia and secondary HPT [19]. Summary score and the specific domains of Bodily Pain and General Health Perception. Vitamin D sterols are frequently used to control sec- Conclusion. Combining results from 4 clinical trials, random- ondary HPT and have been shown to be effective in ization to cinacalcet led to significant reductions in the risk suppressing parathyroid hormone (PTH) [22–24] and of parathyroidectomy, fracture, and cardiovascular hospitaliza- improving bone histology [22, 25]. Despite the use of tion, along with improvements in self-reported physical func- vitamin D, a large fraction of ESRD patients have refrac- tory HPT [21]. Moreover, vitamin D enhances intestinal Keywords: calcimimetics, cinacalcet, outcomes, PTH, secondary hyper- absorption of calcium and phosphorus, complicating the parathyroidism. management of mineral metabolism [26]. Cinacalcet HCl is a calcimimetic agent that binds the calcium-sensing re- Received for publication April 1, 2005 and in revised form April 30, 2005 ceptor (CaR) of the parathyroid gland, resulting in dimin- Accepted for publication May 12, 2005 ished PTH secretion [27]. Cinacalcet acts by allosterically modulating the CaR, enhancing the sensitivity of the CaR C 2005 by the International Society of Nephrology to extracellular calcium and, thus, exerting a suppressive 1793 1794 Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients effect on PTH secretion [27]. Several published studies Study subjects have demonstrated the efficacy of cinacalcet compared The randomized clinical trials included in this anal- with placebo in lowering PTH concentrations in ESRD ysis had similar inclusion and exclusion criteria. Each patients with secondary HPT [28–31]. In contrast with required that eligible subjects were ≥18 years old, ex- vitamin D, when using cinacalcet the reduction in PTH hibited an intact PTH level ≥300 pg/mL and an albumin- secretion has been accompanied by simultaneous reduc- corrected serum calcium ≥8.4 mg/dL, and had received × × tion of the calcium phosphorus product (Ca P), serum hemodialysis 3 times per week for a minimum of 1 to calcium, and phosphorus [28–30]. 3 months or peritoneal dialysis for ≥1 month. In 2 of the The phase 2 and phase 3 studies comparing cinacal- phase 3 trials, intact PTH >800 pg/mL and Ca × P >70 cet with placebo administered to subjects receiving stan- mg2/dL2 were stratification variables. In these 2 studies, dard care for hyperphosphatemia and secondary HPT the number of subjects with intact PTH >800 pg/mL was were designed with sufficient power to answer questions limited to no more than 20% (similar to the percentage related to biochemical end points (e.g., proportion of observed in the general dialysis population), although this subjects with end-of-study PTH concentrations below limitation was not a requirement in the other trials. 250 pg/mL or with a reduction of 30% or more from Exclusion criteria included parathyroidectomy or my- baseline). However, these individual studies were not ocardial infarction within 3 to 6 months of the start designed to evaluate the effects of cinacalcet on mor- of treatment and change of vitamin D therapy within bidity (including hospitalization and fracture), mortality, 30 days of the start of treatment. Additional exclusion or other outcomes believed to be related to the severity criteria included the use of flecainide, lithium, thori- of secondary HPT, such as physical function and health- dazine, haloperidol, or tricyclic antidepressant (except for related quality of life (HRQOL). Data for these clinical amitriptyline) therapy within 21 days of the start of the end points were obtained for safety evaluation in selected trial, gastrointestinal disturbances that could impair the phase 2 and all phase 3 clinical trials, all of which shared absorption of the study drug, the existence of an unstable similar subject inclusion and exclusion criteria and vir- medical condition, and pregnancy or nursing. tually all basic design elements. Herein we present com- The studies were approved by the Independent Ethics bined results from these clinical trials. Committee or the Institutional Review Board, as appro- priate, at each study center, and were conducted in accor- dance with the principles of the Declaration of Helsinki. All subjects provided written informed consent. METHODS Study design Study selection All trials were randomized, double-blind, and placebo- We analyzed data pooled from all clinical trials inves- controlled. Subjects were randomized by a computer- tigating the approved dose range of cinacalcet (30 to generated randomization system. For the 2 phase 180 mg) with at least 6 months of follow-up. One 3 studies in hemodialysis subjects, 1:1 randomization was 12-month phase 2 trial and 3 6-month phase 3 trials were stratified by baseline PTH and Ca × P. For the phase 3 included. A 6-month extension trial of participants in 2 study enrolling hemodialysis and peritoneal dialysis sub- of the phase 3 studies was also included. The study de- jects, a 3:1 ratio (cinacalcet:placebo) was used for ran- sign, including study drug dosing, was similar across all domization, which was stratified by dialysis modality, and studies included in this analysis and is described below. within the hemodialysis subjects by baseline PTH. The The phase 2 trial was performed in the United States and phase 2 study utilized no stratification for the randomiza- Europe and treated 48 subjects at 17 sites. The 3 phase 3 tion. Matching placebos were used, and the blinds were trials were performed in North America (63 sites with 410 maintained through the use of numbered study drug bot- subjects), Europe, and Australia (62 sites with 331 sub- tles. The phase 2 study had a 24-week titration phase and jects), and North America and Australia (60 sites with 395 a 28-week assessment phase. The first 2 phase 3 stud- subjects). The extension trial included subjects from the ies used 12-week titration phases, while the third used a first 2 phase
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