Pam Harrison

June 10, 2014

AMSTERDAM — In hemodialysis patients with secondary hyperparathyroidism, the calcimimetic cinacalcet improves time to death and cardiovascular (CV) end points, but only in those 65 years and older, a new analysis of data from the EVOLVE trial shows.

"We planned this subanalysis of EVOLVE before the trial started because we wanted to see what effect age might have on the treatment effect of cinacalcet," said Patrick Parfrey, MD, professor of medicine at Memorial University in St. John's, Newfoundland, Canada.

"We found that the effect modification by age could be explained by differences in baseline CV risk between younger and older patients, the differential application in younger and older patients of cointerventions to reduce parathyroid hormone, and differences in the diminished power to observe an effect in younger and older patients." Dr. Parfrey told Medscape Medical News.

He presented the study results here at the European Renal Association-European Dialysis and Transplant Association 51st Congress.

EVOLVE Study

Because disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to vascular calcification in patients with chronic kidney disease, EVOLVE investigators hypothesized that cinacalcet would reduce the risk for death and nonfatal CV events in hemodialysis patients with secondary hyperparathyroidism.

In the multinational, prospective, double-blind, randomized study, cinacalcet was compared with placebo in hemodialysis patients with moderate to severe hyperparathyroidism.

Of the 3883 patients enrolled in the trial, 74% were younger than 65 years and 26% were 65 years and older.

The primary composite end point was time to death, myocardial infarction, hospitalization for unstable angina, heart failure, and peripheral vascular events.

Previous results from EVOLVE demonstrated that, after 21.2 months of follow-up, the primary composite end point was similar in the cinacalcet and placebo groups (48.2% vs 49.2%), as reported by Medscape Medical News.

For the current analysis, Dr. Parfrey and his colleagues set out to determine whether outcomes are altered by the use of cointerventions to reduce parathyroid hormone, including renal transplantation and parathyroidectomy, or age-based differences in CV risk.

At baseline, as expected, younger patients had much less CV disease than older patients, and the prevalence of diabetes was significantly lower in younger patients than in older patients (29% vs 46%).

Rates of parathyroidectomy and kidney transplantation — both of which interrupt severe hyperparathyroidism — were compared between younger and older patients. "There was a 3-fold increased rate of kidney transplantation in younger than in older patients, as well as a 3-fold greater use of parathyroidectomy in younger than in older patients," Dr. Parfrey reported. The greater use of cointerventions in younger patients could have influenced outcomes.

In the older group, cinacalcet improved time to death by 27% (P < .001) and the primary composite CV endpoint by 26% (P < .001).

A difference in the treatment effect was seen between the younger and older patients categorized by history of CV disease at baseline.

Table. Hazard Ratio for Treatment Effect of Cinacalcet, Compared With Placebo

Age Group CV Disease at Baseline No CV Disease at Baseline
Younger 0.84 0.97
Older 0.66 0.83

 

Approximately two-thirds of patients in the placebo group were treated with cinacalcet after the development of severe unremitting hyperparathyroidism. This skewed results and decreased the study's power to observe treatment effects in younger patients.

"If you evaluate the effect of cinacalcet on the basis of why we give it in the first place, which is to prevent severe unremitting hyperparathyroidism, the drug worked in both age groups," Dr. Parfrey reported. It reduced the risk for "severe unremitting hyperparathyroidism by over 50% in all patients."

"Our analysis supports the use of cinacalcet in older patients with continuing hyperparathyroidism who are at high CV risk. It also supports cinacalcet use in younger patients at high CV risk if they are not candidates for renal transplantation or parathyroidectomy," he said.

Hypothesis-Generating Analysis

Although the data presented are "interesting," this is more of a "hypothesis-generating" analysis, said Patrick Rossignol, MD, PhD, professor of therapeutics at the University Hospital Centre of Nancy in France. Further study and more evidence is needed before practice changes.

However, Dr. Rossignol acknowledged that there is, as yet, no therapy to prevent CV events in hemodialysis patients, which is clearly needed.

"Given the fact that cinacalcet use was shown to be safe in the EVOLVE trial, one might consider using it, especially in elderly hemodialysis patients with continuing hyperparathyroidism, to prevent cardiovascular complications" until more robust data become available, he concluded.

The study was funded by Amgen. Dr. Parfrey and Dr. Rossignol have disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress: Abstract TO013. Presented June 3, 2014.

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