Vitamin D Supplementation in Chronic Stable Heart Failure
Condition: Heart Failure; Vitamin D Deficiency
MeSH terms: Heart Failure; Vitamin D Deficiency
Study type: Interventional
Phase: Phase 3

Summary: 
      In cross-sectional and prospective cohort studies, vitamin D deficiency is associated with
      increased mortality, cardiovascular events including sudden cardiac death and stroke,
      diabetes, hypertension and impaired function of the immune and musculoskeletal system. The
      action of vitamin D on the cardiovascular system regulates cardiac function, endothelial and
      vascular smooth muscle, and, the renin-angiotensin system. Treatment with sufficiently high
      doses of vitamin D may represent a promising and inexpensive intervention option. To date,
      there are few data on the effect of cholecalciferol treatment in patients with chronic heart
      failure. The primary objective of this study is to investigate whether oral vitamin D
      supplementation improves chronic heart failure (measured with the surrogate parameter of
      NT-proBNP levels at month 0 and 6).
    

Detailed description: 
      A growing body of data suggests that low vitamin D levels may adversely affect cardiovascular
      health. For many cardiovascular events, seasonal variability with peak incidence in the
      winter months is proven. This may be attributable at least in part to declining body stores
      of vitamin D beginning with September. Recently, there have been several case reports about
      severe cardiomyopathy caused by vitamin D deficiency, especially in dark-skinned children who
      had low vitamin D levels. The heart is an important target organ for vitamin D, both on a
      genomic and nongenomic level. Myocytes express the vitamin D receptor and several models of
      hypertension in animal studies have shown that vitamin D treatment is able to prevent cardiac
      hypertrophy [9-10]. Vitamin D seems to inhibit activation of the cardiac renin-angiotensin
      system as well as the expression of genes involved in the development of myocardial
      hypertrophy. There is accumulating evidence that vitamin D deficiency may be an important
      factor in the development of congestive heart failure and sudden cardiac death.

      In chronic hemodialysis patients, vitamin D supplementation has been associated with
      reduction of cardiac hypertrophy and a reduction of QT dispersion, the latter being
      considered a major risk factor for sudden cardiac death. A small study from 1984 showed an
      improvement in left ventricular function after treatment with cholecalciferol in hemodialysis
      patients. A recent study from our group has reported a negative correlation of 25(OH)D levels
      with NT-pro-BNP levels, New York Heart Association functional classes and impaired left
      ventricular function. Furthermore, hazard ratios for death attributable to heart failure and
      sudden cardiac death were 2.84 and 5.05, respectively, when patients with 25(OH)D <25ng/ml
      were compared with those having serum levels of 25(OH)D >75 ng/ml [11]. The anti-inflammatory
      properties of vitamin D also appear to play a role in congestive heart failure, as studied in
      a recent interventional trial. In animal models, vitamin D deficiency was proven to be
      associated with developing myocardial hypertrophy and fibrosis with aberrant cardiac
      contractility and relaxation. Moreover, vitamin D deficiency can raise parathyroid hormone
      secretion, which in turn may increase insulin resistance and be associated with the
      development of diabetes, hypertension and inflammation. In summary, vitamin D seems to exert
      a multitude of different effects all working in concert to protect the vascular and cardiac
      system by influencing various hierarchical levels of biologic response.

      Recently, a randomized controlled trial in a subgroup of patients with heart failure(n=105, ≥
      70 years) was able to demonstrate a significant decrease in BNP levels at 10 and 20 weeks,
      while the primary endpoint "functional capacity" and quality of life did not differ between
      intervention and placebo group.

      Because in this latter trial, even the intervention group did not reach normal vitamin D
      levels, we will use a higher dose of vitamin D given in shorter intervals.
    

Intervention name(s): Cholecalciferol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Cholecalciferol 90,000 IU followed by weekly 24,000 IU for 24 weeks of vitamin D3 (total dose: 666,000 IU); Placebo in matching volumes
Other intervention name(s): Vitamin D; Herbal Oil
Intervention MeSH terms: Vitamin D; Cholecalciferol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: vitamin D deficiency, vitamin D insufficiency, heart failure