The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial

Abstract

Background and objectives: The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients.

Design, setting, participants, & measurements: Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.

Results: Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.

Conclusions: In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

Trial registration: ClinicalTrials.gov NCT00345839.

Keywords: CKD; cardiovascular disease; hemodialysis; hyperparathyroidism; mineral metabolism.

Figure 1.

Kaplan-Meier time-to-event curves for cointerventions that reduce parathyroid hormone (PTH). Time to kidney transplantation (A), parathyroidectomy (B), and use of commercial cinacalcet (C) in the groups randomized to placebo (dotted line, <65 years; dashed line, ≥65 years) and to cinacalcet (solid line, <65 years; bold line, ≥65 years) by age group.

Figure 2.

Kaplan-Meier time-to-event curves for clinical end points. Time to the primary composite cardiovascular end point (A), to death (B), and to severe unremitting hyperparathyroidism (C) in the groups randomized to placebo (dotted line, <65 years; dashed line, ≥65 years) and to cinacalcet (solid line, <65 years; bold line, ≥65 years) by age group.

Figure 3.

Unadjusted relative hazards (± 95% confidence intervals) by decade for the primary composite end point (cinacalcet versus placebo) using intention-to-treat analysis.