Cinacalcet May Reduce Cardiovascular Risk for Older Kidney Disease Patients: EVOLVE Re-Analysis

At Kidney Week 2014, Patrick Parfrey, MD, Professor of Nephrology at Memorial University of Newfoundland, Canada, presented a re-analysis of a large study of the calcimimetic cinacalcet. This re-examination of data from EVOLVE (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), a trial of cinacalcet for individuals with chronic kidney disease (CKD) and moderate to severe secondary hyperparathyroidism, showed some cardiovascular protective benefits for older individuals.

Secondary hyperparathyroidism can occur in CKD when the kidney loses its ability to produce active metabolites of vitamin D, and reduces phosphorus excretion. Serum calcium plummets as more and more calcium is bound as calcium phosphate, and parathyroid hormone (PTH) soars as the body tries to increase serum calcium. Bone loss as well as a host of biochemical and endocrine disruptions may ensue. Cinacalcet seeks to interrupt the progression to severe unremitting hyperparathyroidism by mimicking calcium to the calcium-sensing receptors that control PTH levels.

Although PTH levels in CKD are associated with increased all-cause mortality, it has not been clear the extent to which disordered calcium and phosphorus metabolism contributes to increased cardiovascular risk. It is known that the increased vascular calcification seen in CKD contributes to a higher rate of atherosclerotic events. Further, the protein FGF23, an agent in phosphorus metabolism, is also affected by cinacalcet; FGF23 also seems to play a role in mediating cardiovascular risk in CKD.

The EVOLVE trial was a randomized, double blind, event-driven, placebo controlled trial enrolling nearly 4,000 hemodialysis-receiving patients with moderate to severe hyperparathryroidism. Patients in both the cinacalcet and placebo arm continued to be eligible for other conventional methods to treat hyperparathyroidism. Over a 64-month period, the study population was followed, and analysis of the intention-to-treat population examined a primary composite endpoint consisting of time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event.

Published results for the unadjusted intention-to-treat population failed to show a significant reduction in the primary outcome for the cinacalcet population, with a non-significant 0.93 hazard ratio (HR) for those on cinacalcet.

Parfrey, arguing that patient age was both a confounder and a modifier of the results, presented a post hoc analysis re-examining the effect of cinacalcet with age stratification. He first noted that the placebo group was, on average, about a year older than the intervention group. After adjustment for this difference, the primary endpoint was reduced by 12%, a significant result.

By looking at the oldest cohort of patients, those 65 and older, the adjusted HR for risk of the primary endpoints dropped to 0.7, also reaching significance. Overall, for the older population, there was a 27% reduced chance of death for those using cinacalcet compared with the older placebo group.

Examining characteristics that differed between the older and the younger population, Parfrey noted that the older population had a higher prevalence of cardiovascular disease, making it more likely that this group would see a benefit. Further, younger patients were more likely to receive other medical or surgical interventions that would reduce PTH levels, as was the placebo group.

When those with CVD in each age group were identified, cinacalcet also showed increased benefit for the older group — a HR of 0.84 for the younger group, compared with 0.66 for the older patients with CVD.

EVOLVE, said Parfrey, also showed a decrease for the cinacalcet arm in the incidence of non-atherosclerotic events, such as heart failure and left ventricular dysfunction. Returning to the putative role of FGF23 in mediating CVD risk in CKD, Parfrey noted that 64% of the cinacalcet group had reduced FGF23 levels; this reduction may represent a previously unrecognized pathway for benefit in reducing CVD risk.

Sharp questioning after Parfrey’s talk centered on whether moving away from the intention-to-treat analysis of the original EVOLVE data takes away from the real-life applicability of the study. Merely observing a biological effect, it was noted, does not necessarily reflect benefits that will be seen in clinical practice. Parfrey responded by reiterating his belief that the more subtle analysis that accounts for the confounding and modifying effect of age gives clinicians a better appreciation for the populations cinacalcet is most likely to benefit. However, he conceded, a new clinical trial with predefined analyses for age, CVD status, and accounting for the role of FGF23 is sorely needed.