Top-line results for the EVOLVE study using cinacalcet (Sensipar) in patients with end-stage renal disease (ESRD) were reported last week. In this phase 3 placebo-controlled randomized trial of 3,883 patients with secondary hyperparathyroidism, those on active treatment received a titrated dose of cinacalcet starting at 30 mg/day up to 180mg and were followed for approximately 4 years. Patients were evaluated for the composite primary outcome of all-cause mortality or first non-fatal cardiovascular event, including myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event. Despite very promising biochemical outcomes from earlier studies with cinacalcet, the reduction in the primary outcome, while numerically positive, was not statistically significant. A more detailed analysis of this study will be completed once the paper is published.
The evolution of cinacalcet as potential treatment for patients with ESRD was always exciting to watch since the molecule elegantly controls nearly all biochemical parameters correctly in patients with ESRD. Earlier in the product's life-cycle, the drug received a warning to avoid its use in patients with earlier stage CKD (i.e. those not on dialysis) because the reduction in PTH achieved with it led to an increase in serum phosphate - a development deemed by many to be a dangerous outcome. Cinacalcet then was relegated to use in those with ESRD, a practice that may have limited its ultimate potential. It is important to remember however, that such a practice means that we are certain that potential PTH reductions achievable with cinacalcet are less important than increases in serum phosphate. And while this may indeed be the case, we simply do not know, and no amount expert opinion can answer this question without a properly done randomized trial in phosphorus lowering or without a study looking at comprehensive surrogate marker interventions in patients with CKD, like the famous STENO trial in diabetes. Could reducing PTH in a patient with CKD not on dialysis be helpful despite a rise in phosphate? Possibly. But phosphate interventions continue trump all others in nephrology without any conclusive evidence to do so.
And so the EVOLVE study is neutral, but we must continue to test all currently unproven hypotheses without bias. If the administration of statins could be randomized in dialysis patients to test whether LDL lowering is important in this population than certainly every unproven surrogate marker in nephrology is open to the same evaluation. And on the heels of this study, nephrology as a discipline will not evolve until we end this systematic bias.