Jana B. Ernst

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.

25-Hydroxyvitamin D, 1,25-Dihydroxyvitamin D and Postoperative Outcome in Cardiac Surgery

CONTEXT Several cohort studies have reported U-shaped or inverse J-shaped associations between circulating 25-hydroxyvitamin D [25OHD] and clinical outcomes. OBJECTIVE We aimed to investigate in cardiac surgical patients the association of preoperative 25OHD and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels with the risk of major adverse cardiac and cerebrovascular events (MACCE). DESIGN A prospective cohort study of adult cardiac surgical patients in 2012-2013 was used. SETTING The study was conducted at the Heart and Diabetes Center North Rhine-Westphalia, Germany. PATIENTS A total of 3371 adult patients participated in the study. INTERVENTION None Measurements: The main outcome measure was MACCE until discharge. We categorized vitamin D metabolite levels into subgroups and performed multivariable-adjusted logistic regression analysis to estimate odds ratios (ORs) of MACCE. Moreover, we performed multiple regression analysis to assess the association of 25OHD and circulating 1,25(OH)2D3 with preoperative parameters. RESULTS As compared with patients in the 25OHD reference category (75-100 nmol/L), the multivariable-adjusted odds ratios (OR) of MACCE was significantly higher in patients with deficient 25OHD levels (< 30 nmol/L) (OR = 2.06 [95%CI: 1.24-3.43]), but was comparable in patients with 25OHD levels > 100 nmol/L (OR = 1.16 [95% CI: 0.56-2.37]). Poor kidney function was an important predictor of high 25OHD (>100 nmol/L) and low 1,25(OH)2D3 levels. 1,25(OH)2D3 was not independently associated with the incidence of MACCE. CONCLUSIONS In cardiac surgical patients, deficient but not high 25OHD levels are independently associated with the risk of MACCE. Cohort studies should consider potential interrelationships between kidney function, circulating vitamin D metabolite levels, and clinical outcome.

Effect of Vitamin D or Activated Vitamin D on Circulating 1,25-Dihydroxyvitamin D Concentrations: A Systematic Review and Metaanalysis of Randomized Controlled Trials

BACKGROUND Evidence is accumulating that circulating 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations are inversely related to overall mortality. METHODS We searched PubMed, Embase and ISI Web of Science for randomized controlled trials with a control group receiving a placebo instead of vitamin D/activated vitamin D and performed a metaanalysis to evaluate the effect of oral vitamin D/activated vitamin D on circulating 1,25(OH)2D concentrations using a random effects model. RESULTS We included 52 vitamin D intervention groups (4796 individuals) and 14 intervention groups with activated vitamin D (668 individuals). Vitamin D supplements increased circulating 1,25(OH)2D by 12.2 pmol/L (95% CI, 7.8-16.5 pmol/L) and 18.8 pmol/L (95% CI, 9.2-28.4 pmol/L) if only studies with a low risk of bias in study design and reporting were considered (n = 18). There was significant heterogeneity among studies (Cohrans Q P < 0.001, I(2) = 91%). The incremental effect was larger in studies using vitamin D alone compared with coadministration of calcium supplements (18.6 pmol/L; 95% CI, 12.7-24.4 pmol/L vs 4.9 pmol/L; 95% CI, -0.4 to 10.2 pmol/L; P = 0.001), and if quantification was performed with RIA vs other methods (17.1 pmol/L; 95% CI, 11.1-23.1 pmol/L vs 6.9 pmol/L; 95% CI, 1.0-12.8 pmol/L; P = 0.02). Activated vitamin D increased the mean circulating 1,25(OH)2D by 20.5 pmol/L (95% CI, 8.3-32.7 pmol/L; P = 0.04). Again, there was evidence for significant heterogeneity among studies (Cochran Q = 85.4; P < 0.001; I(2) = 87%), but subgroup analysis did not identify parameters significantly influencing the increment in 1,25(OH)2D concentrations. CONCLUSIONS Both vitamin D and activated vitamin D significantly increase circulating 1,25(OH)2D concentrations, but in vitamin D users this increase is suppressed by calcium coadministration.

Vitamin D Supplementation and Hemoglobin Levels in Hypertensive Patients: A Randomized Controlled Trial

Epidemiological evidence suggests that circulating 25-hydroxyvitamin D (25OHD) levels are inversely associated with hemoglobin (Hb) levels and anemia risk. We evaluated whether vitamin D supplementation improves Hb levels and reduces anemia risk in hypertensive patients. Two hundred patients with 25OHD levels <75 nmol/L who attended the Styrian Vitamin D Hypertension Trial were included, of whom 188 completed the trial. Patients randomly received 2800 IU vitamin D3 daily or a matching placebo for eight weeks. Initially, the prevalence of anemic status (Hb levels <12.5 g/dL) and deficient 25OHD levels (<30 nmol/L) was 6.5% and 7.5%, respectively. All anemic patients had 25OHD levels >50 nmol/L. The mean (95% confidence interval) vitamin D effect on Hb levels was 0.04 (−0.14 to 0.22) g/dL (P = 0.661). Moreover, vitamin D treatment did not influence anemic status significantly (P > 0.999). Likewise, vitamin D had no significant effect on Hb levels in the subgroups of anemic patients or in patients with initial 25OHD levels <30 nmol/L. In conclusion, a daily vitamin D supplement of 2800 IU for eight weeks did not improve Hb levels or anemic status in hypertensive patients. Future trials should focus on anemic patients with deficient 25OHD levels (e.g., <30 nmol/L). This trial is registered with clinicaltrials.gov [NCT02136771].

Measurement of Circulating 1,25-Dihydroxyvitamin D: Comparison of an Automated Method with a Liquid Chromatography Tandem Mass Spectrometry Method

Background. The clinical relevance of circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) is probably underappreciated, but variations in the measurement of this difficult analyte between different methods limit comparison of results. Methods. In 129 clinical samples, we compared a new automated assay with a commercially available liquid chromatography tandem mass spectrometry (LC-MS/MS) kit. Results. Median (interquartile range) 1,25(OH)2D concentrations with the automated assay and the LC-MS/MS method were 26.6 pg/mL (18.5–39.0 pg/mL) and 23.6 pg/mL (16.1–31.3 pg/mL), respectively (P = 0.001). Using the method-specific cut-offs for deficient 1,25(OH)2D levels (<20 pg/mL for the automated assay and <17 pg/mL for the LC-MS/MS method), the percentage of patients classified as 1,25(OH)2D deficient was 28.7% and 27.1%, respectively. However, concordance between the two methods for deficient levels was only 62% and the concordance correlation coefficient was poor (0.534). The regression equation resulted in an intercept of −1.99 (95% CI: −7.33–1.31) and a slope of 1.27 (95% CI: 1.04–1.52) for the automated assay. The mean bias with respect to the mean of the two methods was −3.8 (1.96 SD: −28.3–20.8) pg/mL for the LC-MS/MS method minus the automated assay. Conclusions. The two methods show only modest correlation and further standardization is required to improve reliability and comparability of 1,25(OH)2D test procedures.

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.

Calciotropic and Phosphaturic Hormones in End-Stage Heart Failure Patients Supported by a Left-Ventricular Assist Device

Background Calcium and phosphate are central for myocardial contractility and energy metabolism, and low levels of the calciotropic hormone 1,25-dihydroxyvitamin D (1,25(OH)2D), as well as high levels of the phosphaturic hormone fibroblast growth factor (FGF)-23, are independently associated with poor clinical outcome in heart failure (HF) patients. We therefore aimed to investigate the postoperative time course of the aforementioned hormones in HF patients supported with a left-ventricular assist device (LVAD) implant. Methods For the present study, stored biobank plasma samples of 69 patients, collected before LVAD implantation (t0) and 12 days (t1), 30 days (t2), 83 days (t3), and 300 days (t4) post-intervention, were used to measure circulating FGF-23, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), 1,25(OH)2D, and kidney function. Results Most patients were male and had baseline INTERMACS levels and cardiac index values ≤ 3 and ≤ 2.7 L/min/m2, respectively. There were significant time effects on estimated glomerular filtration rate (eGFR), FGF-23 and 1,25(OH)2D, but not on PTH or 25OHD. Notably, eGFR values increased and FGF-23 levels decreased only transiently, whereas 1,25(OH)2D increased continuously until t4. The rise in 1,25(OH)2D was largely influenced by those patients who survived the first post-implant year, and was not seen in non-survivors. Variations in 1,25(OH)2D levels could only partly be explained by eGFR values or FGF-23, 25OHD, and PTH levels (multiple R2 = 0.305;P<0.001). Conclusions The present study indicates that LVAD implantation has only transient effects on circulating FGF-23 levels, but is associated with a continuous increase in circulating 1,25(OH)2D levels, especially in survivors.

Vitamin D Deficiency and Anemia in Heart Failure

Both vitamin D deficiency and anemia are prevalent in heart failure patients, and are independent predictors of poor clinical outcome in these patients. Experimental studies have established several mechanisms regarding how vitamin D may influence erythropoiesis. In addition, observational studies indicate an inverse association of low circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with anemia. The first non-randomized intervention trials with vitamin D (metabolites) support the assumption of beneficial vitamin D effects on erythropoiesis. Nevertheless, randomized controlled trials are still warranted to prove whether the relationship between vitamin D and anemia risk is causal.