Daniel M. Keller, PhD

November 08, 2012

SAN DIEGO, California — Cinacalcet does not reduce the risk for death or major cardiovascular (CV) events among patients with moderate-to-severe secondary hyperparathyroidism who were on hemodialysis. Glenn Chertow, MD, MPH, professor of medicine and chief of the division of nephrology at Stanford University School of Medicine in California, presented results of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial in San Diego, California, at Kidney Week 2012. An article was published in the New England Journal of Medicine to coincide with the presentation.

The trial was based on the hypothesis that secondary hyperparathyroidism in patients with chronic kidney disease may contribute to vascular calcification and that the calcimimetic agent cinacalcet might reduce CV risk. "The general impetus behind EVOLVE was to determine whether a therapy which interrupted this process of secondary hyperparathyroidism might result in an improvement in some of the complications from which patients suffer," Dr. Chertow told Medscape Medical News.

EVOLVE enrolled hemodialysis patients with a serum intact parathyroid hormone (iPTH) of 300 pg/mL (the level at which mortality rate appears to increase) or greater, calcium of 8.4 mg/dL or greater, and a calcium phosphorus product of 45 mg2/dL2 or greater. Patients were randomly assigned in a double-blind manner to placebo plus standard of care (n = 1935) or to cinacalcet plus standard of care (n = 1948), which generally included vitamin D sterols and phosphate binders.

Cinacalcet Showed No Cardiovascular Benefit

A Kaplan-Meier analysis on an intention-to-treat (ITT) basis showed no significant benefit for the primary composite endpoint (time to all-cause mortality or nonfatal CV events). Of 1948 patients on cinacalcet, 938 (48.2%) reached the primary composite endpoint vs 952 (49.2%) of 1935 in the placebo group. The median duration of study drug exposure was 21.2 months for cinacalcet and 17.5 months for placebo. There was also no difference in all-cause mortality on an ITT basis (hazard ratio [HR] = 0.94; 95% confidence interval [CI] 0.85 - 1.04; P = .249).

When the primary composite endpoint results were adjusted for age, a 12% benefit for cinacalcet emerged (HR = 0.88; 95% CI 0.81 - 0.97; P = .007). A multivariable (best fit) model gave similar results as did adjustment for all baseline characteristics.

Patients on cinacalcet had a 56% prolonged time to first parathyroidectomy compared with the placebo group (HR = 0.44; 95% CI 0.36 - 0.54; P < .001). Similarly, the cinacalcet group had a longer time to a first episode of severe, unremitting hyperparathyroidism (HR = 0.43; 95% CI 0.37 - 0.50; P < .001). But there was no advantage to cinacalcet in time to a first clinical fracture (HR = 0.89; 95% CI 0.75 - 1.07; P = .218).

High Rate of Drug Discontinuation

There was a high and equivalent rate of study drug discontinuation in both the cinacalcet and placebo groups. Dr. Chertow noted that hemodialysis patients take about 20 pills a day, adverse effects are likely, and it is difficult for them to know which medication is causing an adverse effect. Of note, one reason for study drug discontinuation in either group was to go on commercially available cinacalcet.

Adverse events in the cinacalcet arm were, overall, more frequent than in the placebo arm. There was a 7-fold increase in hypocalcemia (P < .001) and a 2-fold increase in nausea and vomiting (P < .001), for example.

Dr. Chertow concluded that in an unadjusted ITT analysis, the study showed only a 7% reduction in the risk for death or major CV events using cinacalcet vs placebo; he called this a "non-significant and non-definitive" result "in patients with moderate to severe secondary hyperparathyroidism undergoing dialysis." Again, when adjusting for age or age plus other variables, there was a "nominally significant" 12% reduction in these risks. However, in light of the higher rate of adverse events with cinacalcet, he advised that any potential benefits of cinacalcet must be weighed against the risks and discomforts.

"Disappointing" Results

In an accompanying editorial, Vlado Perkovic, MBBS, PhD, and Bruce Neal, MBChB, PhD, from the George Institute for Global Health at the University of Sydney, Australia, called the findings "disappointing," adding that the immaterial significance of the secondary analysis "hint[s] that the trial may have missed the detection of a real benefit" and "point[s] to a missed opportunity to identify or exclude a protective therapy for patients undergoing dialysis."

More important, Dr. Perkovic and Dr. Neal said, were the high rates of discontinuations and treatment crossover during the trial, with almost two-thirds of cinacalcet patients discontinuing active drug and 1 fifth of the placebo group starting on commercially available cinacalcet. The resulting reduction in a difference in PTH levels between the groups "substantially reduced the power of the trial to test its hypotheses," they wrote.

Harsh Words for Regulatory Authorities and Nephrologists

Finally, the editorialists criticized regulatory authorities for approving cinacalcet without a clearly demonstrated benefit on hard clinical endpoints, which they called a "system failure." And they criticized the nephrology community for widely prescribing the drug without clear evidence of patient-level benefits. They recommended a better regulatory strategy for the future.

Although EVOLVE does not give any solid information about cinacalcet in terms of protection against CV events (and raises concerns about its side effect profile), it provides some insight into how regulatory processes, guideline development, and clinical practice should be changed. "If such goals can be achieved, even a negative result from the EVOLVE trial will have had a very positive effect," the editorialists wrote.

Session moderator Julie Ingelfinger, MD, senior consultant in pediatric nephrology at Massachusetts General Hospital and professor of Pediatrics at Harvard Medical School in Boston, Massachusetts, and deputy editor of the New England Journal of Medicine, commented to Medscape Medical News, "I think one has to be very conservative in this study. It's a… frustrating study in that there may well be a signal there... [but] nobody can say what … this truly mean[s]."

Dr. Ingelfinger agrees with the editorialists: some of the confounding factors that make interpretation difficult were the crossovers to commercial cinacalcet or off of the study drug entirely, reducing the power of the trial and weakening the conclusions.

In summary, Dr. Ingelfinger said, "I don't think the drug is known not to have an effect, so you can't really make a conclusion, and I think it is always a mistake to call a positive secondary result a true positive. I totally agree with the EVOLVE study group in being very conservative" in their interpretations of the results.

The trial was funded by Amgen. Dr. Chertow has received consulting fees or honoraria and travel support from Amgen. He is on the board of directors of Satellite Healthcare, is on the scientific advisory board for DaVita Clinical Research, is a consultant to Reata Pharmaceuticals, and has stock options in Allocure, Ardelyx, Home Dialysis Plus, PuraCath, and Thrasos. Dr. Neal is a consultant for Roche, Takeda, Servier, Johnson & Johnson, Merck, Schering Plough, Respironics, Medtronic, and Bupa Australia. He has received honoraria for speaking at scientific conferences from Abbott, AstraZeneca, Novartis, Pfizer, the Pharmacy Guild of Australia, and Roche. He has received grants from Baxter, Johnson & Johnson, Novartis, Roche, Mundipharma, Mitsubishi Tanabe, and has supervised fellows supported by research fellowships from Amgen. Dr. Perkovic has consulted for Baxter, Abbott, Boehringer Ingelheim, Vitae, and Johnson & Johnson. He has received clinical trial support from Baxter, Johnson & Johnson, Novartis, Roche, AstraZeneca, and has supervised fellows supported by Amgen. He has received speaker's fees from Servier, Roche, and AstraZeneca. Both Dr. Neal and Dr. Perkovic serve on the Trial Steering Committee for CANVAS, a trial of a glucose-lowering agent. Dr. Perkovic also serves on a Trial Steering Committee for a trial of steroids in IgA nephropathy. Dr. Ingelfinger was not involved in the study and had no relevant financial disclosures other than being a deputy editor of the journal in which the study is published.

Kidney Week 2012: Abstract # HI-OR03. Presented November 3, 2012.