A 3 year post-intervention follow-up on mortality in advanced heart failure (EVITA vitamin D supplementation trial).

AIMS: Vitamin D supplementation is widely used in the clinical setting, but its effects on mortality and cardiovascular outcomes in patients with heart failure are unclear. This paper reports outcome data that were collected during follow-up of 3 years after closure of the EVITA trial (a 3 year randomized, placebo-controlled, intervention study with 4000 IU vitamin D daily in patients with advanced heart failure), to capture potential latency effects of vitamin D supplementation on clinical outcomes. METHODS AND RESULTS: The prespecified primary endpoint was overall mortality. Secondary endpoints included hospitalization, mechanical circulatory support implantation, high urgent listing for heart transplantation, and heart transplantation. For group comparisons, we used Cox regression models with a time-dependent categorical covariate. The calculated net difference in circulating 25-hydroxyvitamin D between the vitamin D and placebo groups dropped from 60.9 nmol/L at the end of the active study period to 3.2 nmol/L at the end of the post-intervention period. During the entire 6 year period, 73 patients (36.5%) died in the placebo group and 76 (38.8%) in the vitamin D group. Out of these 149 patients, 36 and 39 died during the first 3 years, and 37 and 37 during the second 3 years, respectively. The hazard ratio (HR) for mortality in the vitamin D versus the placebo group was 1.06 [95% confidence interval (CI): 0.68-1.66] for the first 3 years and 1.07 (95% CI: 0.68-1.70) for the 3 year post-intervention follow-up. Compared with the placebo group, the HRs for hospitalization and for mechanical circulatory support implant were significantly higher in the vitamin D group during vitamin D supplementation (HR = 1.31, 95% CI: 1.01-1.68 and HR = 2.01, 95% CI: 1.08-3.76, respectively) but not after vitamin D discontinuation (HR = 1.10, 95% CI: 0.62-1.94 and HR = 0.99, 95% CI: 0.38-2.56, respectively). There was no significant time-dependent effect on the risk of high urgent listing for heart transplantation and heart transplantation. CONCLUSIONS: No beneficial latency effects of vitamin D supplementation on overall mortality could be demonstrated. Instead, the disappearance of unfavourable findings in the vitamin D group (higher HRs for hospitalization and for mechanical circulatory support implant) after vitamin D discontinuation supports the assumption of adverse vitamin D effects on the cardiovascular system at doses of 4000 IU daily.

Vitamin D supplementation does not prevent the testosterone decline in males with advanced heart failure: the EVITA trial.

PURPOSE: Observational studies indicate a positive association between circulating 25-hydroxyvitamin D (25OHD) and testosterone (T) concentrations. Because low 25OHD concentrations and T deficiency are considered to be a generalized phenomenon in patients with advanced heart failure (HF), we aimed to investigate whether vitamin D supplementation has beneficial effects on T indices in these patients. METHODS: In a pre-specified secondary analysis of the EVITA (effect of vitamin D on mortality in heart failure) randomized controlled trial, we analyzed in male subjects with 25OHD concentrations < 75 nmol/L the effect of a daily vitamin D3 supplement of 4000 IU for 3 years (n = 71) vs. placebo (n = 62) on total T (TT), sex hormone-binding globulin (SHBG), free T (fT), and bioactive T (BAT). We assessed changes from baseline until study termination and between-group differences at study termination. RESULTS: 25OHD increased in the placebo group from 36.6 nmol/L by 9.2 nmol/L (95% CI 3.2-15.1 nmol/L; P = 0.003) and in the vitamin D group from 36.5 nmol/L by 63.9 nmol/L (95% CI 52.6-75.3 nmol/L; P < 0.001), with a significant between-group difference at study termination (P < 0.001). TT and SHBG concentrations did not change significantly, neither in the placebo group nor in the vitamin D group (P = 0.845-0.082), but concentrations of fT and BAT declined significantly in both groups (P = 0.025-0.008). At study termination, there were no between-group differences in TT (P = 0.612), SHBG (P = 0.393), fT (P = 0.861), or BAT (P = 0.960). CONCLUSIONS: In male patients with advanced HF and low 25OHD concentrations, a daily vitamin D3 supplement of 4000 IU for 3 years did not prevent the decline in testosterone indices.

Daily Supplementation with 4000 IU Vitamin D3 for Three Years Does Not Modify Cardiovascular Risk Markers in Patients with Advanced Heart Failure: The Effect of Vitamin D on Mortality in Heart Failure Trial.

BACKGROUND/AIMS: We aimed to investigate the effect of a moderately high vitamin D dose on lipid parameters and biochemical markers of vascular calcification (VC) in patients with established cardiovascular disease. METHODS: We included in this pre-specified secondary analysis of a randomized controlled trial 161 patients with advanced heart failure and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L (vitamin D group: n = 80; placebo group: n = 81), who received a daily vitamin D3 supplement of 4,000 IU for 3 years. We assessed between-group differences of the lipid parameters total-cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides, and the VC markers fetuin-A and non-phosphorylated undercarboxylated matrix gla protein (MGP) at study termination, with adjustment for baseline values. RESULTS: Lipid parameters, the percentage of patients with dyslipoproteinemia, and VC markers did not differ significantly between groups at study termination (p values: 0.395-0.939). Likewise, vitamin D achieved no significant treatment effect on these markers in subgroup analyses in patients with 25OHD concentrations < 30 nmol/L, nonusers of lipid-lowering drugs, or diabetic patients (p values: 0.245-0.998). CONCLUSION: Our data indicate that vitamin D does not improve the lipid profile and does not influence the calcification inhibitors fetuin-A and non-phosphorylated undercarboxylated MGP in patients with advanced heart failure.

Effects of Vitamin D Supplementation on Renin and Aldosterone Concentrations in Patients with Advanced Heart Failure: The EVITA Trial.

OBJECTIVE: 1,25-Dihydroxyvitamin D (1,25([OH]2D) is considered to be a negative endogenous regulator of the renin-angiotensin-aldosterone system (RAAS), but the effect of vitamin D supplementation on the RAAS is inconclusive. DESIGN: In this prespecified secondary analysis of a randomized controlled trial, we assessed in 165 patients with heart failure (vitamin D group: n = 83; placebo group: n = 82) the effect of three years of vitamin D supplementation with 4000 IU daily on parameters of the RAAS (renin and aldosterone) and on circulating 1,25(OH)2D, plasma phosphate, and fibroblast growth factor (FGF)-23. We assessed age- and baseline-adjusted between-group differences at study termination. RESULTS: Almost all patients were under treatment with beta-blockers, inhibitors of the RAAS, and diuretics. Initially, the frequency of concentrations above the laboratory-specific reference range (renin: >23.9 mIU/L; aldosterone: >232 ng/L) in the vitamin D and placebo group was 87.7% and 92.7%, respectively (renin), and 24.1% and 32.5%, respectively (aldosterone). Vitamin D increased adjusted 1,25(OH)2D concentrations significantly (mean treatment effect and 95% CI: 18.3 pmol/L,7.3 to 29.3 pmol/L; P < 0.001) but had no significant effects on phosphate (0.18 mmol/L, -0.00 to 0.35 mmol/L; P = 0.051), FGF-23 (685 RU/mL, -213 to 1585 RU/mL; P = 0.134), renin (312 mIU/L, -279 to 902 ng/L; P = 0.298), or aldosterone (-0.19 ng/L, -5.09 to 4.70 ng/L; P = 0.938). Vitamin D supplementation was, however, associated with an increase in renin concentrations in the subgroup with baseline 25-hydroxyvitamin D below 30 nmol/L (n = 67; 1365 mIU/, 343 to 2386 mIU/L; P = 0.010). CONCLUSIONS: In patients with advanced heart failure treated according to evidence-based guidelines, vitamin D supplementation did not significantly influence parameters of the RAAS in the entire study cohort but was associated with an increase in plasma renin concentrations in the subgroup with low baseline 25-hydroxyvitamin D concentrations.

Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily.

AIMS: Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. METHODS AND RESULTS: Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). CONCLUSION: A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov Idenitfier: NCT01326650.

The role of vitamin D for cardiovascular disease and overall mortality.

In recent years, it became increasingly clear that vitamin D exerts important pleiotropic effects, besides its well-known effects on extracellular calcium homeostasis and on bone metabolism. This article gives a comprehensive overview of studies on cardiovascular and all-cause mortality with a focus on the most recent data. 25-hydroxyvitamin D (25[OH]D) is the best indicator of vitamin D status. Low 25(OH)D levels are highly prevalent among general populations. Prospective cohort studies support the assumption that poor vitamin D status, e.g., 25(OH) D levels below 30 nmol/l, is independently associated with CVD mortality risk. However, support from randomized controlled trials for a beneficial vitamin D effect on CVD risk is still lacking. Meta-analyses of prospective cohort studies indicate beneficial vitamin D effects on overall mortality as well. There is also likely evidence from meta-analyses of randomized controlled trials that vitamin D may improve overall mortality in elderly people. Therefore, it is reasonable to supplement institutionalized individuals and other people with deficient 25(OH)D levels with daily vitamin D amounts of 20 microg. However, it is also noteworthy that prospective cohort studies provide evidence for an inverse J-shaped association between vitamin D status and overall mortality, indicating increased overall mortality risk not only at deficient 25(OH)D levels but also at 25(OH)D levels above 125 nmol/l. Although there is evidence that high 25(OH)D levels sometimes reflect low availability of the vitamin D hormone 1,25-dihydroxyvitamin D, future studies are still needed to clarify the association of high 25(OH)D levels with high mortality rates more detailed.

Association of 25-hydroxyvitamin D with anemia risk in patients scheduled for cardiac surgery.

INTRODUCTION: There is emerging data that vitamin D plays a role in erythropoiesis. Low 25-hydroxyvitamin D (25OHD) levels may therefore be a risk factor for anemia in patients scheduled for cardiac surgery. METHODS: We investigated 4428 consecutive cardiac surgical patients to determine an association between anemia (hemoglobin concentration <12.5 g/dL, 27.1% of the study cohort) and circulating 25OHD. RESULTS: In patients with severe vitamin D deficiency (25OHD < 12.5 nm), mean hemoglobin concentrations were 0.80 g/dL lower compared with patients with adequate 25OHD levels (50.0-100 nm). Hemoglobin levels were not significantly different at 25OHD levels above 100 nm compared with 50.0-100 nm. In multivariable-adjusted logistic regression analyses, the odds ratios for anemia of the groups with severe and moderate vitamin D deficiency (12.5-29.9 nm) were 1.70 (95% CI:1.09-2.63) and 1.41 (95% CI:1.02-1.96), respectively, compared with patients who had circulating 25OHD levels of 75-100 nm. Prevalence of deficient circulating 25OHD levels was highest in anemia of chronic kidney disease. CONCLUSION: This cross-sectional study demonstrates an independent association between vitamin D status and anemia risk with optimal 25OHD levels of 75-100 nm. Randomized controlled trials are needed to clarify whether this association is causal.

Safety issues of vitamin D supplementation.

Vitamin D deficiency is a re-emerging global health problem, which is primarily due to inadequate vitamin D synthesis in the skin. Supplement use is an effective measure to improve vitamin D status. However, some safety issues have to be considered, which are highlighted in this review article: The concept of vitamin D safety consists of two models, the safe tolerable upper intake level (UL) method, and the idea of adequate circulating 25-hydroxyvitamin D (25[OH]D) levels. Oral vitamin D intakes up to 250 µg/d have not been associated with harm. Hypercalcemia, the hallmark of vitamin D intoxication, may only occur if circulating 25(OH)D levels are consistently above 375-500 nmol/l. However, some observational studies indicate that already circulating 25(OH)D levels > 125 nmol/l are related to an increased morbidity and mortality risk. Therefore, the Institute of Medicine has set the UL for adults at 100 µg/d, and the adequate circulating 25(OH)D level at 50 to 125 nmol/l. In clinical practice, oral vitamin D dosing has to consider that the increment in circulating 25(OH)D depends on baseline 25(OH)D levels and the person's body weight. It is reasonable to assess 25(OH)D before and 3-6 months after initiation of oral vitamin D administration and to adjust the dose, if necessary. In future, two issues have to be clarified: First, would it be more appropriate to define instead of a fixed UL a variable UL, based on the individual's body weight? Second, what are the underlying mechanisms, if any, for potentially harmful vitamin D effects at circulating 25(OH)D levels between 125 and 375 nmol/l.

Vitamin D deficiency is an independent predictor of anemia in end-stage heart failure.

Both, anemia and vitamin D deficiency are prevalent in patients with heart failure. According to recent evidence, vitamin D may stimulate erythropoiesis. We measured circulating 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH](2)D) and hemoglobin (Hb) in a cross-sectional study in 364 end-stage heart failure patients awaiting cardiac transplantation, of whom 52.6% met the criteria for anemia (Hb < 13 g/dl in males and <12 g/dl in females). None of the patients were on erythrocyte-stimulating agents. Of the study cohort, 87.8% had 25(OH)D concentrations below 50 nmol/l. The mean Hb concentrations were significantly reduced in the lower tertiles of 25(OH)D and 1,25(OH)(2)D (P < 0.001). In multivariate-adjusted logistic regression analyses, the odds ratios for anemia of the lowest tertile of 25(OH)D (<18 nmol/l) and 1,25(OH)(2)D (<40 pmol/l) were 2.69 (1.46-5.00) and 4.08 (2.18-7.62) compared with their respective highest tertile (>32 nmol/l and >70 pmol/l). Patients with severe dual deficiency of 25(OH)D and 1,25(OH)(2)D had an odds ratio for anemia of 9.87 (95% CI 3.59-27.1) compared with patients in the highest tertile for both vitamin D metabolites. Circulating 1,25(OH)(2)D was directly related to circulating 25(OH)D levels and kidney function (P < 0.001), and inversely associated with C-reactive protein (P = 0.020). Our data demonstrate that vitamin D deficiency is independently associated with low Hb values and anemia in end-stage heart failure. Circulating 1,25(OH)(2)D is a better predictor of anemia than circulating 25(OH)D. Prospective randomized studies with administration of vitamin D (metabolites) will have to clarify if the association of vitamin D deficiency with anemia is causal.