Active vitamin D therapy does not reduce the risk for cardiovascular events in patients receiving hemodialysis (HD) who have not yet developed secondary hyperparathyroidism (SHPT), according to new study findings published online ahead of print in JAMA.

The efficacy of active vitamin D in HD has been assumed based on observational studies for the most part. Tetsuo Shoji, MD, PhD, of Osaka City University in Japan, and colleagues conducted the J-DAVID (Japan Dialysis Active Vitamin D) trial to test the merits of vitamin D therapy in HD. They randomly assigned 976 patients (median age 65 years; 40% women) from 108 dialysis centers in Japan to oral alfacalcidol (0.5 μg daily), a vitamin D receptor activator (VDRA), or usual care with no VDRAs. Patients had baseline serum levels of intact parathyroid hormone (iPTH) of 180 pg/mL or less, calcium of 10.0 mg/dL or less, and phosphate of 6.0 mg/dL or less. Patients were permitted to receive phosphate binders and cinacalcet as part of their usual medical care.

During a median 4 years of follow-up, cardiovascular events occurred in 21.1% of the intervention group and 17.9% of the control group, a nonsignificant difference between the groups. Cardiovascular events broadly included myocardial infarctions, congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, sudden cardiac death, coronary revascularization, and leg artery revascularization. All-cause mortality also did not differ significantly between groups.

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VDRA therapy appears ineffective in this population, and further analyses suggest that it might even be harmful. Both the treatment and control arms experienced similar proportions of adverse events, including cardiovascular events, infection, and malignancy.

“VDRAs may only benefit patients with secondary hyperparathyroidism by suppressing phosphate/calcium mobilization from bone,” Dr Shoji and the team suggested. “Second, the cardiovascular effects of VDRAs may vary depending on the degree of calcium load.” A majority of patients received dialysate calcium and calcium carbonate at baseline.

An accompanying editorial questioned the generalizability of the study results to the US population. Alfacalcidol is not available in the United States, and patient management differs from that in Japan (e.g., Japanese guidelines target lower iPTH levels).

“Thus, the J-DAVID trial warns against the embrace of unexamined treatments, such as early use of VDRAs, that are commonly used among patients undergoing hemodialysis and have the potential for unanticipated harm,” Rasheeda K. Hall, MD, MBA, MHS, and Julia J. Scialla, MD, MHS, of Duke University School of Medicine in Durham, North Carolina, commented. “Ultimately, deciding whether results of the J-DAVID trial should reduce enthusiasm for VDRA use in the prevention of CVD for all patients with ESKD who are undergoing hemodialysis, or only for patients undergoing hemodialysis with low PTH levels, will remain a topic of debate.”

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The J-DAVID Investigators. Effect of oral alfacalcidol on clinical outcomes in patients without secondary hyperparathyroidism receiving maintenance hemodialysis: The J-DAVID randomized clinical trial. JAMA. 2018;320(22):2325-2334. DOI:10.1001/jama.2018.17749 (Published online December 11, 2018)

Hall RK and Scialla JJ. Vitamin D receptor agonists for patients undergoing hemodialysis. JAMA. 2018;320(22). (Published online December 11, 2018)