**13. Future directions**

*Vitamin D Deficiency*

supplementation [66].

**11. Renal disease**

related mortality [69].

this population [70].

in CKD patients [71, 72].

**12. Conclusions**

A recent randomized, controlled trial assessed the effects of 50,000 IU of weekly vitamin D or placebo for 6 months on various measures of physical performance (primary endpoint: peak VO2; secondary endpoints: 6-Minute Walk test, timed get up and go test, isokinetic muscle strength) in patients with heart failure. The study failed to demonstrate any benefits, despite considerable increases in

In VINDICATE, a double-blind, randomized, placebo-controlled trial, subjects with systolic dysfunction (ejection fraction (EF) ≤ 45%) and vitamin D deficiency (<20 ng/mL) were randomized to 4,000 IU of vitamin D3 or placebo. At 12 months, there was no significant difference in 6-minute walking distance (primary endpoint), but there was significant improvement in left ventricular (LV) systolic function and a reduction in LV end diastolic and end systolic diameter with active

In the EVITA trial, 400 patients with heart failure were randomized to receive 4,000 IU of vitamin D or placebo daily for 3 years. There was no benefit of supplementation on the primary endpoint of all-cause mortality. Additionally, secondary endpoint analysis suggested that vitamin D supplementation was associated with an

increased frequency of implantation of mechanical circulatory support [67].

Observational studies show that there are potential benefits to vitamin D supplementation in patients with chronic kidney disease (CKD). In a meta-analysis of some of these studies, it was determined that receiving treatment with any vitamin D derivative reduces all-cause mortality as well as CV mortality [68]. In another, more recent, meta-analysis of observational studies, it has been shown that vitamin D treatment may pose benefits toward reducing all-cause mortality and CV

To further assess some of the available randomized, clinical trials for renal patients, a meta-analysis was done to test the efficacy of vitamin D supplementation in these patients. The 13 trials used for the meta-analysis showed no significant benefits for serious adverse CV events, all-cause mortality, or CV related mortality in CKD patients who supplemented with vitamin D. Unfortunately, there is a lack of patient level data relating to patients with CKD, making it difficult to draw any conclusions regarding the effects of vitamin D supplementation on CV health in

In many of the previous studies in patients with CKD, the dosage of vitamin D has been limited in order to protect patients from developing hypercalcemia. Additionally, a lack of standardization in vitamin D formulations has made it especially difficult to compare results in different trials. Larger randomized trials with well-defined primary outcomes need to be conducted in order to further define vitamin D's effect on CVD in renal patients. In 2025, the SIMPLIFIED trial is expected to conclude and expectantly give insight into the effects of vitamin D supplementation on hard endpoints of all-cause mortality and CV related mortality

Epidemiologic, observational and laboratory evidence have implicated vitamin D deficiency in the pathogenesis and complications of CVD. This lent extensive biologic plausibility to the theory that vitamin D levels would be an effective target

serum 25(OH)D levels in the active treatment group [65].

**220**

Based on the findings in the most recent clinical trials, it appears that the last chapter may have been written regarding the role of vitamin D for CVD prevention in the general population. However, many questions still remain and will likely fuel ongoing investigation and debate. Was the follow-up in these recent trials long enough? Do large trials randomizing by baseline vitamin D status need to be conducted since the mean vitamin D levels in VITAL and VIDA were both above the deficient threshold of 20 ng/mL? [9, 10]. Are there benefits to vitamin D repletion for heart failure outcomes? What is the true benefit of vitamin D repletion on CVD outcomes in the chronic kidney disease and dialysis population? These questions and others regarding both CVD and other chronic disease states will likely keep the book open on vitamin D for the foreseeable future.
