The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis

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. ConclusionsIn 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.

Long–term mortality after parathyroidectomy among chronic kidney disease patients with secondary hyperparathyroidism: a systematic review and meta-analysis

“…11,12 Moreover, routine cinacalcet therapy reduces the need for PTx in dialysistreated adults and lowers iPTH levels, but does not improve all-cause or cardiovascular mortality. 13 According to a systematic review, however, cinacalcet increases risks of nausea, vomiting and hypocalcemia, suggesting harms may outweigh benefits. 14 In these cases, PTx is still needed by a significant proportion of dialysis patients with mineral disturbances.…”

Pharmacological Management of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease

“…a negative study). However, in the prespecified subgroup analysis, a 30% reduction in primary outcome was found in the older (≥ 65 years) patients who also had more cardiovascular co-morbidities (124). Secondary end points analysis showed no difference in fracture rate but parathyroidectomy rate was half in the intervention group compared to that in the control group.…”

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

“…The relative hazard for the primary end point using ITT was 0.74 (95% CI, 0.63 to 0.86) in the older group and 0.99 (95% CI, 0.88 to 1.11) in the younger group (19). There was a 27% reduction in mortality in patients age .65 years (P,0.001).…”

“…After it became apparent that the overall (blinded) event rate was ,20.8%, we extended the trial by 16 months to allow for accrual of the requisite number of events. The actual annual event rate in the placebo group was 15.5% (19).…”

“…The test of treatment3age interaction was significant (P50.03 with age used as a continuous variable; P50.01 with age dichotomized at 65 years). The age modification of the treatment effect was partly related to (1) three-fold higher rates of kidney transplantation and PTX in younger patients, cointerventions that limited detection of a treatment effect; (2) lower rate of CV disease at baseline in younger patients, which limited the potential of cinacalcet to decrease CV events rates; and (3) lower CV event rates that decreased the power to observe an effect (19).…”