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Active Vitamin D No Help for CV Events in Select CKD Patients (CME/CE)

Action Points

  • Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did notreduce the risk of a composite measure of select cardiovascular events.
  • The researchers cautioned against the use of vitamin D receptor activators for patients with end-stage kidney disease without secondary hyperparathyroidism receiving maintenance hemodialysis.

CME Author: Zeena Nackerdien

Study Authors: Tetsuo Shoji, Masafumi Fukagawa, et al.

Target Audience and Goal Statement:

Nephrologists and primary care physicians

The goal was to learn more about results from The Japan Dialysis Active Vitamin D (J-DAVID) trial, a randomized, open-label, blinded-endpoint, multicenter clinical trial.

Questions Addressed:

A growing understanding of the roles of vitamin D and its native form, calcitriol, has led to the suggestion that these key agents act via vitamin D receptors (VDRs) to contribute to parathyroid hormone (PTH) suppression, enhanced calcium absorption, and the maintenance of vasculature, immune system, and other tissues. Impaired activation of vitamin D by the kidneys may be implicated in the pathogenesis of mineral bone disorder in chronic kidney disease (CKD). Additionally, “Deficiency in calcitriol, and the resultant decreased activation of the VDR, may contribute to vascular smooth muscle proliferation and cardiac hypertrophy, endothelial dysfunction, thrombosis, and other abnormalities which cumulatively increase the risk of mortality,” noted Daniel W. Coyne, MD in a 2007 Renal and Urology News article.

The J-DAVID trial was designed to address these questions:

  • Can the observational association, irrespective of parathyroid hormone (PTH) levels, found between the use of active vitamin D sterols and lower risk of all-cause mortality in patients receiving hemodialysis be replicated in randomized trials?
  • Will vitamin D receptor activators (VDRAs) reduce cardiovascular (CV) events and deaths in patients treated with hemodialysis who did not have secondary hyperparathyroidism?

Synopsis and Perspective:

Greater levels of albuminuria and decreased glomerular filtration rates (GFRs) are independently linked to death, CV events, and the rate of end-stage kidney disease (ESKD). . According to the 2012 National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guideline, initiation of both peritoneal dialysis and hemodialysis should take into account organ function, symptoms, and other complications of advanced kidney disease. More than 2 million people with CKD receive dialysis or a kidney transplant worldwide to stay alive.

Evidence from the literature shows that there was a higher prevalence of CV disease (CVD) in dialysis patients, and that death due to CVD in this population was 10 to 30 times higher than in the general population.

Patients on dialysis may also experience vitamin deficiencies because of reduced appetites, restricted diets, drugs and comorbidities that could interfere with vitamin absorption, altered metabolic pathways due to uremia, and intradialytic losses. Synthesis of 1α,25(OH)2D3, the biologically active form of vitamin D, also known as calcitriol, by renal 1α-hydroxylase is tightly regulated by the levels of plasma 1α,25(OH)2D3, calcium, and PTH.

Active forms of vitamin D — calcitriol, paricalcitol, and doxercalciferol — are also known as VDRAs. They have been mainly used in nephrology as a treatment for secondary hyperparathyroidism, an elevation in PTH due to renal failure.

Tetsuo Shoji, MD, PhD, of Osaka University in Japan, and colleagues randomly assigned 976 patients to receive oral alfacalcidol (0.5 µg per day) or usual care without VDRAs (n=481). Baseline serum levels of intact PTH, calcium, and phosphate were ≤ 180 pg/mL, ≤ 10 mg/dL, and ≤6 mg/dL, respectively. They were allowed to temporarily stop alfacalcidol to stay within 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 VDRA. Usual care included phosphate binders and cinacalcet (an agent that reduces calcium in the blood).

Patients in the usual-care group were asked not to use VDRAs, but they were allowed if clinicians determined they were necessary under published guidelines.

The primary composite outcome of CV events included atherosclerotic CVD events, such as myocardial infarction, stroke, aortic dissection, amputation due to peripheral vascular disease, and coronary or peripheral revascularization. Hospitalization for congestive heart failure and cardiac sudden death were also included in this endpoint. The secondary outcome was the evaluation of all-cause mortality. The median follow-up period was 4 years.

The difference between the two study groups during the follow-up period was non-significant in that 21.1% in the intervention group versus 17.9% in the usual-care group experienced the primary outcome of CV events for an absolute difference of 3.25% (95% CI −1.75% to 8.24%) and a hazard ratio 1.25 (95% CI 0.94-1.67, P=0.13). All-cause mortality did not differ between the two groups (18.2% active treatment vs 16.8% control, HR 1.12, 95% CI 0.83-1.52, P=0.46). The rate of serious adverse events were generally similar between both groups (76% vs 79.2% control), with CV events making up the majority of serious events.

“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,” the researchers noted.

They added that this randomized trial was challenging to conduct because half the patients wouldn’t receive a VDRA during the trial — against routine practice. But the researchers circumvented this by only including patients that wouldn’t necessarily require a VDRA due to intact PTH levels below the maximum limit of the target range recommended by Japanese clinical practice guidelines.

In an accompanying editorial, Rasheeda Hall, MD, and Julia Scialla, MD, both of Duke University School of Medicine in Durham, North Carolina, 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.

Source Reference: JAMA, Dec. 11, 2018; DOI:10.1001/jama.2018.17749

Study Highlights: Explanation of Findings

Compared with usual care, oral alfacalcidol did not reduce the risk of the primary composite measure of select CV events in study participants. The investigators cautioned against the use of VDRAs for patients with ESKD without secondary hyperparathyroidism receiving maintenance hemodialysis.

The editorialists praised the trial saying it addressed “a critical gap in the literature” and agreed that “combined 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.”

Within the study context, VDRA use may have limited inflammation and vasoactive hormones and increased vascular calcification inhibitors. Although the confidence intervals for the primary analysis reasonably exclude a meaningful clinical benefit, they do not exclude the possibility of meaningful harm among patients with relatively low PTH levels who are undergoing VDRA therapy.

The unanswered question is whether the results can be interpreted within the context of U.S. practice. The overall mineral metabolism management of patients with ESKD differs in Japan versus the U.S. Alfacalcidol, a prodrug of calcitriol, is widely used in many countries, but is not available in the U.S.

Guideline recommendations regarding lower intact PTH ranges differ among countries: 60 pg/mL to 240 pg/mL in Japanese Society for Dialysis Therapy (JDST) guidelines, and about 150 pg/mL to 600 pg/mL in international and U.S. guidelines.

“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,” Hall and Scialla stated in Renal and Urology News. “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.”

Original story for MedPage Today by Kristen Monaco

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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