Alfacalcidol does not reduce the risk for cardiovascular events in patients without secondary hyperparathyroidism undergoing maintenance hemodialysis compared with usual care, the Japan Dialysis Active Vitamin D (J-DAVID) trial has found. But experts question the generalizability of the findings.

During a median of 4 years, the composite outcome of select cardiovascular events was 21.1% in those who took oral alfacalcidol, a vitamin D receptor agonist (VDRA), compared with 17.9% in the usual-care group, a difference that was not statistically different.

“[O]ral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these,” the researchers write.

The study, by Tetsuo Shoji, MD, PhD, from the Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Japan, and colleagues, was published online December 10 in JAMA.

The study was conducted in Japan, and the results are not generalizable to other countries, Rasheeda K. Hall, MD, MBA, MHS, and Julia J. Scialla, MD, MHS, from the Department of Medicine, Duke University School of Medicine, Durham, North Carolina, write in an accompanying editorial.

“Although the use of phosphate binders, VDRAs, and cinacalcet in Japan are comparable to the use in the United States, dialysate calcium and selection of calcium-based vs non–calcium-based phosphate binders tends to be higher in Japan. These patterns were observed in the J-DAVID trial, with approximately 70% of participants using dialysate calcium of 3.0 mEq/L and approximately 80% using calcium-based phosphate binders,” Hall and Scialla explain.

“These practices may be so different from those in the United States and internationally that generalization is not feasible,” they continue.

No Difference in Cardiovascular Outcomes

Vitamin D activation is impaired and cardiovascular risk is elevated in patients with chronic kidney disease. Observational studies have suggested that VDRAs reduce this risk, but the approach had not been tested in randomized trials.

Therefore, Shoji and colleagues conducted a randomized, open-label, blinded endpoint trial that compared the effect of the oral VDRA alfacalcidol with usual care (no VDRAs) on cardiovascular events in patients without secondary hyperparathyroidism receiving maintenance hemodialysis at 108 dialysis centers. For the patients in the study, serum intact parathyroid hormone levels were ≤180 pg/mL.

The investigators randomly assigned 976 patients to receive either alfacalcidol, beginning at a dose of 0.5 μg per day (n = 495) or usual care (n = 481). The intention-to-treat analysis included 964 patients, of whom 944 (97.9%) completed the trial. The median age of the participants was 65 years, and 386 were women (40.0%).

“All participants were eligible to receive any medications other than VDRAs, including phosphate binders and cinacalcet, for standard medical care as recommended by the JSDT [Japanese Society for Dialysis Therapy] Clinical Practice Guidelines,” the researchers explain.

Cardiovascular events, the primary composite outcome, occurred in 103 of 488 patients (21.1%) in the alfacalcidol group, compared with 85 of 476 patients (17.9%) in the usual-care group (absolute difference, 3.25%; 95% confidence interval [CI], −1.75% to 8.24%; hazard ratio [HR], 1.25; 95% CI, 0.94 – 1.67; P = .13). This difference was not statistically significant.

The secondary outcome of all-cause mortality did not differ significantly between the groups (18.2% vs 16.8%, respectively; HR, 1.12; 95% CI, 0.83 – 1.52; P = .46).

Among those in the alfacalcidol group, 76.0% experienced serious adverse events (SAEs), including cardiovascular-related (40.8%), infection-related (13.1%), and malignancy-related SAEs (4.5%).

Among those in the usual-care group, 79.2% experienced SAEs, including events that were cardiovascular- (40.1%), infection- (13.2%), and malignancy-related (4.4%).

“The number of cardiovascular SAEs was higher than the number of occurrences of the primary outcome because some participants had more than 2 cardiovascular SAEs,” the researchers explain.

Predefined laboratory abnormalities differed between the two groups. Corrected serum calcium levels >10.0 mg/dL and phosphate levels >6.0 mg/dL occurred more frequently in the group that received alfacalcidol compared with the control group. Intact parathyroid hormone levels >240 pg/mL occurred less commonly, especially during the first year of follow-up.

Generalizability May Be Limited

“[T]he results cannot be generalized to patients with secondary hyperparathyroidism or to non-Japanese populations, particularly not to US patients undergoing hemodialysis, who have much higher levels of intact PTH [parathyroid hormone] than the participants of this trial,” the researchers note.

Hall and Scialla reiterate that point. “As the J-DAVID investigators acknowledge, VDRAs may plausibly yield different results when accompanied by less calcium loading in the form of dialysate and exogenous calcium,” they write.

The editorialists say that although the researchers excluded patients “with clear indications or contraindications for VDRAs,” approximately one third of participants crossed over during the study; 35% of patients in the usual-care group and 32% of those in the alfacalcidol group dropped out of their assigned treatment. The study did not account for this in power calculations, they explain.

“In addition, the composite cardiovascular end point in the J-DAVID trial was broad. Although this broad end point may improve power for the study, the pathophysiology of many of the end point components, such as sudden cardiac death, peripheral amputation, and stroke, including hemorrhagic stroke, may be heterogeneous and not clearly modified by 1,25[OH]2D-responsive pathways,” Hall and Scialla observe.

“Future studies are needed, both observational and randomized, to understand who should be treated with VDRAs, to what biochemical target levels patients should be treated, and what therapeutic combinations of VDRAs and mineral metabolism cointerventions should be used to prevent CVD in patients with ESKD [end-stage kidney disease] undergoing hemodialysis,” they conclude.