Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial

Abstract

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%.

Keywords: CKD; hemodialysis; hyperparathyroidism; osteodystrophy; renal.

Figure 1.

Unadjusted fracture rates by site, age, and treatment group. Fractures are more common at nonhip cortical sites compared with the hip, and are more common in patients aged ≥65 years. Bar graphs represent the mean±SD.

Figure 2.

Cumulative incidence of fractures. Cumulative incidence of clinical fractures in patients aged <65 years (top) and aged ≥65 years (bottom). Patients randomized to cinacalcet are shown with the solid line, and patients randomized to placebo are shown with the dashed line.

Figure 3.

Forest plot of treatment effect of cinacalcet on clinical fracture rate by prespecified baseline characteristics using lag-censoring analysis. HR, hazard ratio.

Figure 4.

Forest plot of treatment effect of cinacalcet on clinical fracture rates by concomitant medications using lag-censoring analyses. HR, hazard ratio.