Vitamin D supplementation of 4000 IU daily and cardiac function in patients with advanced heart failure: The EVITA trial

https://doi.org/10.1016/j.ijcard.2019.01.027Get rights and content

Highlights

  • The effect of vitamin D on cardiac function is hotly debated but available data are inconclusive.

  • We investigated the effect of a daily vitamin D3 supplement of 4,000 IU for three years on cardiac function.

  • Vitamin D supplementation may not improve cardiac function in all patients with heart failure, but probably in patients aged ≥ 50 years.

Abstract

Background

Data regarding the effects of vitamin D on cardiac function are inconclusive.

Methods

In a post-hoc analysis of the EVITA (Effect of vitamin D on mortality in heart failure) trial, we investigated whether a daily vitamin D3 supplement of 4000 IU for three years affects echocardiography parameters like left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and LV ejection fraction (LVEF) in patients with advanced heart failure (HF) and 25‑hydroxyvitamin D levels <75 nmol/L. Of 400 patients enrolled, 199 were assigned to vitamin D and 201 to placebo. We assessed time × treatment interaction effects using linear mixed models and analyzed in subgroups vitamin D effects at 12 and 36 months post-randomization using analysis of covariance with adjustments for baseline values.

Results

At baseline, values of LVEDD, LVESD, and LVEF were 67.5 ± 10.5 mm, 58.9 ± 12.0 mm, and 30.47 ± 10.2%, respectively. There were no time × treatment interaction effects on LV echocardiographic parameters in the entire study cohort, neither at 12 months nor at 36 months post-randomization (P-values > 0.05). However, in the subgroup of patients aged ≥50 years, vitamin D treatment was associated with an increase in LVEF of 2.73% (95%CI: 0.14 to 5.31%) at 12 months post-randomization (n = 311). The increase was slightly attenuated to 2.60% (95%CI: −2.47 to 7.67%) at 36 months post-randomization (n = 242).

Conclusion

Our data indicate that vitamin D supplementation does not significantly improve cardiac function in all patients with advanced HF. However, vitamin D probably improves LV function in HF patients aged ≥50 years.

Introduction

Heart failure (HF) continues to be a medical problem in aging societies with globally almost 23 million people being affected [1]. The illness usually results in cardiac dilatation and decreasing left ventricular ejection fraction (LVEF) [2]. Pharmacologic treatment aims to prevent progressive cardiac hypertrophy and LVEF decline [3], but 5% of patients develop end-stage HF that is refractory to effective medical treatment [4]. Ventricular assist device implants and heart transplantation are the last treatment options for these patients.

Vitamin D may be critical for the heart because vitamin D receptor knockout mice yield elevated production of renin and angiotensin II, hypertension, and cardiac hypertrophy [[5], [6], [7]]. In patients with HF, low circulating 25‑hydroxyvitamin D (25OH) levels (i.e. <75 nmol/L) are prevalent [[8], [9], [10], [11]] and some observational studies indicate an inverse association between circulating 25OHD levels and HF [12,13].

With respect to randomized controlled trials (RCTs), a recent meta-analysis [14] indicated that in patients with HF, vitamin D supplementation may suppress biochemical markers of inflammation. Moreover, based on four studies (303 patients) lasting 12 weeks to 9 months and using vitamin D doses equivalent to 1000 IU to 7143 IU daily, this meta-analysis reported a non-significant increase in LVEF by vitamin D supplementation (weighted mean difference: +4.1% [95%CI: −0.91% to +9.12%], P = 0.11). A more recent RCT in 163 patients with HF and mean circulating 25OHD levels of 37 nmol/L [15] reported a significant improvement in LVEF (difference in mean change: +6.07% [95%CI: +3.20% to +8.94%], P < 0.001) and also in left ventricular (LV) remodelling by daily vitamin D supplementation with 4000 IU for one year.

Since a beneficial vitamin D effect on LVEF would have important consequences regarding prevention and treatment of HF, we aimed to investigate in a post-hoc analysis of the EVITA (effect of vitamin D on mortality in heart failure) trial [16] whether these reported beneficial effects on cardiac function can be confirmed in patients with advanced HF refractory to optimal medical therapy. Further, we expanded the existing knowledge by investigating the effects of vitamin D supplementation on left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) in this population.

Section snippets

Study design and participants

EVITA was a single-center, randomized, placebo-controlled, clinical trial, performed at the Clinic for Thoracic and Cardiovascular Surgery of the Heart- and Diabetes Center North Rhine Westphalia, Bad Oeynhausen, Germany. Study design and main study results have already been published elsewhere [[16], [17], [18], [19], [20]]. Briefly, 400 patients of HF with reduced LVEF participated in the trial. Eligible patients were aged ≥18 to 79 years, had New York Heart Association functional class

Results

Of the 400 study participants, 113 patients dropped out, 75 patients died, and additional 35 patients were lost-to follow-up. At baseline, 12 and 36 months post-randomization LV echocardiographic data were available in 400, 311, and 242 patients for the intention-to-treat analysis, respectively (Fig. 1). Baseline characteristics of the study cohort are presented in Table 1. The vast majority of patients had moderately or severely abnormal LVEF, LVEDD, and LVESD values. Moreover, in both groups

Discussion

The present investigation indicates that a daily vitamin D3 supplement of 4000 IU for three years does not significantly influence LV echocardiography data in a cohort of patients with advanced HF, neither 12 months nor 36 months post-randomization. However, our data also indicate that vitamin D probably improves LV function in patients aged ≥50 years.

In our study, the mean difference in LVEF change between study groups at 12 and 36 months was within the 95% confidence interval of the

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

Acknowledgement

We thank Birgit Drawe and Bärbel Kammel, Institute for Laboratory and Transfusion Medicine, Heart- and Diabetes Center NRW, Ruhr-University of Bochum, Bad Oeynhausen, Germany for their excellent technical assistance.

Funding

The study was sponsored by the Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Germany. The Friede Springer Stiftung (Berlin, Germany) and Merck KGaA (Darmstadt, Germany) provided funding for the study. Merck also provided the study medication. The funding sources were not involved in the study design, collection, analysis, or interpretation of data, or in preparation or submission of the manuscript for publication.

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    This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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