The Clinical Course of Treated Hyperparathyroidism Among Patients Receiving Hemodialysis and the Effect of Cinacalcet: The EVOLVE Trial

Parfrey, Patrick S.; Chertow, Glenn M.; Block, Geoffrey A.; Correa‐Rotter, Ricardo; Drüeke, Tilman B.; Floege, Jürgen; Herzog, Charles A.; London, Gérard M.; Mahaffey, Kenneth W.; Moe, Sharon M.; Wheeler, David C.; Dehmel, Bastian; Trotman, Marie Louise; Modafferi, Dennis; Goodman, William G.

doi:10.1210/jc.2013-2975

Cited by 69 publications

(47 citation statements)

References 20 publications

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“…The baseline characteristics of the population, 20 trial design, 21 disposition of trial participants (Consolidated Standards of Reporting Trials diagram), primary results, 22 and effect on the risk of severe unremitting hyperparathyroidism 23 were previously published. The trial population was diverse in terms of age, sex, race/ethnicity, and comorbidity; the median dialysis vintage was 45.3 months.…”

Section: Baseline Characteristicsmentioning

confidence: 99%

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis

Moe

Abdalla

Chertow

et al. 2015

Journal of the American Society of Nephrology

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177

116

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Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for #64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%. 26: 146626: -147526: , 201526: . doi: 10.1681 Patients with end stage renal disease (ESRD) on dialysis have increased risk of fractures compared with the general population. 1 Fracture incidence rates vary by geographic region, although rates are consistently higher in patients with CKD than matched controls from the same country. [2][3][4][5][6] Depending on the study, 10%-52% of patients receiving dialysis J Am Soc Nephrol

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Section: Baseline Characteristicsmentioning

confidence: 99%

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis

Moe

Abdalla

Chertow

et al. 2015

Journal of the American Society of Nephrology

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177

116

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“…The relative hazard (cinacalcet versus placebo) for severe unremitting HPT was 0.43 (95% CI, 0.37 to 0.50). This relative hazard was similar whether baseline iPTH was mildly or markedly elevated, but the number of events prevented increased as iPTH increased (12).…”

Section: End Points With Selection Biasmentioning

confidence: 70%

“…PTX was a secondary end point in EVOLVE; however, before the start of the study it was evident that the criteria by which physicians selected PTX for the treatment of sHPT varied widely across the world, and the trial protocol provided no criteria for PTX. Factors associated with PTX during the trial indicated selection effects and included younger age, female sex, higher body mass index, markers of comorbidity (no history of valvular disease, angina, or peripheral vascular disease), higher serum calcium, and higher PTH; the use of PTX also varied widely by country of origin (lowest rates were in the United States) (12). In addition, PTX was performed at an advanced phase of sHPT: before PTX the mean PTH level was 1872 pg/ml and the mean serum calcium level was 10.3 mg/dl (2.58 mmol/L) (12).…”

Section: End Points With Selection Biasmentioning

confidence: 99%

Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis

Parfrey¹,

Block²,

Correa‐Rotter³

et al. 2016

Clinical Journal of the American Society of Nephrology

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The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism was assessed in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis, and reporting of the trial, many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting hyperparathyroidism), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower-than-predicted event rate during the trial, development of a prespecified analytic plan that accounted for nonadherence and for cointerventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated before trial initiation, and interpretation of the benefits-to-harms ratio for individual patients. It is likely that many of these issues will arise in the planning of future trials in CKD.

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“…Previous meta-analyses have confirmed that calcimimetic treatment effectively improves significant biochemical parameters of SHPT and enables more patients to achieve common targets (65,66). Other studies and metaanalyses have confirmed that cinacalcet has a significant beneficial effect in preventing parathyroidectomy and hypercalcemia (13,49,59,(65)(66)(67)(68)(69), but these studies also found that cinacalcet increases nausea, vomiting, and hypocalcemia, with relative risks of 2.02 (95% CI, 1.45 to 2.81), 1.97 (95% CI, 1.73 to 2.24), and 6.98 (95% CI, 5.10 to 9.53), respectively (59). Therefore, these are the problems that nephrologists encounter more frequently with the clinical use of cinacalcet, together with PTH oversuppression (5).…”

Section: Cinacalcet Use In Patients With Ckd Treated By Dialysismentioning

confidence: 98%

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism

Bover

Ureña

Ruiz-García

et al. 2016

Clinical Journal of the American Society of Nephrology

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CKD and CKD-related mineral and bone disorders (CKD-MBDs) are associated with high cardiovascular and mortality risks. In randomized clinical trials (RCTs), no single drug intervention has been shown to reduce the high mortality risk in dialysis patients, but several robust secondary analyses point toward important potential beneficial effects of controlling CKD-MBD-related factors and secondary hyperparathyroidism. The advent of cinacalcet, which has a unique mode of action at the calcium-sensing receptor, represented an important step forward in controlling CKD-MBD. In addition, new RCTs have conclusively shown that cinacalcet improves achievement of target levels for all of the metabolic abnormalities associated with CKD-MBD and may also attenuate the progression of vascular and valvular calcifications in dialysis patients. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Tolerance of cinacalcet is limited by frequent secondary side effects such as nausea, vomiting, hypocalcemia and oversuppression of parathyroid hormone, which may cause some management difficulties, especially for those lacking experience with the drug. Against this background, this review aims to summarize the results of studies on cinacalcet, up to and including the publication of the recent ADVANCE and EVOLVE RCTs, as well as recent post hoc analyses, and to offer practical guidance on how to improve the clinical management of the most frequent adverse events associated with cinacalcet, based on both currently available information and personal experience. In addition, attention is drawn to less common secondary effects of cinacalcet treatment and advisable precautions.

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The Clinical Course of Treated Hyperparathyroidism Among Patients Receiving Hemodialysis and the Effect of Cinacalcet: The EVOLVE Trial

Abstract: Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.

Cited by 69 publications

References 20 publications

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis

Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism

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