Supplementation with the vitamin D receptor agonist (VDRA) alfacalcidol in a randomized trial wasn’t effective at reducing cardiovascular events for those on hemodialysis, researchers said.
Compared with patients told not to use VDRAs, those receiving 0.5 μg of oral alfacalcidol per day experienced a similar rate of composite cardiovascular events over 4 years (17.9% control vs 21.1% active; HR 1.25, 95% CI 0.94-1.67, P=0.13), according to Tetsuo Shoji, MD, PhD, of Osaka City University Graduate School of Medicine in Japan, and the Japan Dialysis Active Vitamin D (J-DAVID) randomized clinical trial investigators.
Additionally, the rate of all-cause mortality — the trial’s secondary endpoint — wasn’t significantly different between those on alfacalcidol versus treatment without VDRAs (18.2% active treatment vs 16.8% control; HR 1.12, 95% CI 0.83-1.52, P=0.46), they wrote in the Journal of the American Medical Association.
“Despite the lack of evidence by randomized trials, many nephrologists consider the administration of VDRAs to be mandatory for patients undergoing hemodialysis, based on a number of observational studies that showed associations between VDRA use and lower risk of all-cause mortality and cardiovascular outcomes in participants receiving hemodialysis,” noted the researchers.
They continued, adding that this randomized trial was challenging to conduct due to the fact that half the patients wouldn’t receive a VDRA during the trial — against routine practice — but the researchers were able to circumvent this by only including patients that wouldn’t necessarily require a VDRA due to intact parathyroid hormone (PTH) levels below the maximum limit of the target range recommended by Japanese clinical practice guidelines.
The open-label trial was conducted across 108 Japanese dialysis centers and included nearly 1,000 adults on maintenance hemodialysis without secondary hyperparathyroidism (serum intact PTH levels ≤180 pg/mL). The primary outcome was a composite of fatal and nonfatal cardiovascular events including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, cardiac sudden death, coronary revascularization, and leg artery revascularization occurring within 4 years of follow-up.
At enrollment, all participants had serum calcium levels of ≤10 mg/dL, serum phosphate levels ≤6 mg/dL, and were able to temporarily stop alfacalcidol in order to stay in these target ranges. Alfacalcidol was titrated up to doses ranging from 0.25 to 7.00 μg each week in order to maintain PTH levels ≤180 pg/mL prior to 2012, or ≤240 pg/mL after 2012, according to guidelines. For those receiving the intervention, if intact PTH level exceeded the recommended limit, they were allowed to switch from oral alfacalcidol to another oral or intravenous VDRAs. Control patients were asked not to use VDRAs, but they were allowed if clinicians determined they were necessary under published guidelines.
The rate of serious adverse events were generally similar between both groups (76% vs 79.2% control), with cardiovascular events making up the majority of serious events.
In an accompanying editorial, Rasheeda Hall, MD, and Julia Scialla, MD, both of Duke University School of Medicine in Durham, praised the trial saying it addressed “a critical gap in the literature” and agreed that “[c]ombined with the similar lack of benefit of VDRAs on cardiovascular surrogates in patients with advanced, predialysis CKD, the current evidence does not support use of VDRAs in patients with ESKD and relatively low PTH to prevent CVD.”
But Hall and Scialla also pointed out that the participant pool was limited to patients who wouldn’t typically be prescribed VDRAs. “This focus leaves open the question of whether VDRAs, as currently used to target observationally defined PTH ranges, also help to prevent CVD,” they wrote.
The editorialists noted as well that the findings may not be generalizable to other countries, including the U.S., where alfacalcidol is not available. And, they added, “given the inherent complexity of mineral metabolism physiology, it is always possible to question whether the intervention is delivered too early, too late, with the wrong cointerventions, or to the wrong patient.”
The study was supported by a grant from The Kidney Foundation, Japan, which received donation from Chugai Pharmaceutical. Shoji reported grants from The Kidney Foundation, Japan, during the conduct of the study and fees from Chugai Pharmaceutical, Kyowa Hakko Kirin, Kissei Pharmaceutical, Bayer, Ono Pharmaceutical, and Torii Pharmaceutical outside the submitted work. Other study authors also reported disclosures.
The editorial was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases R01DK111952 and from the National Institute on Aging. Scialla reported received research support from Lilly, Sanofi, and GlaxoSmithKline for clinical event committee activities.