Can Vitamin D Supplementation Benefit Heart Failure Patients?

Heart failure (HF) remains an extremely prevalent condition with an unacceptably high 5-year mortality rate despite significant advancements in pharmacotherapy, such as angiotensin receptor-neprilysin inhibitors, and device therapy, like cardiac resynchronization therapy.

Vitamin D deficiency is common in patients with HF, and several nonrandomized studies have demonstrated an increased risk of new-onset HF and HF-related mortality in those with inadequate vitamin D levels.

Vitamin D is a steroid hormone that modulates gene transcription by binding a nuclear receptor found in numerous tissues, including the heart and vasculature. One of the genes regulated by vitamin D is renin, which is a key neurohormone in the deleterious pathophysiologic milieu that afflict those with HF (eg, sodium and water retention, cardiac remodeling).

Because vitamin D acts as an endogenous inhibitor of renin expression, it represents a potential therapeutic target in patients with HF. In fact, mice models have demonstrated that inadequate vitamin D levels are prone to developing hypertension and ventricular hypertrophy, and that exogenous administration of vitamin D can reverse these detrimental sequelae.¹

These data raise the possibility that vitamin D supplementation in individuals with vitamin D deficiency could improve outcomes in HF. To date, however, few results from randomized, controlled trials have supported this hypothesis. Now, the VINDICATE study has put it to the test.

In this randomized, double-blind, placebo-controlled trial of vitamin D supplementation (4000 IU per day) in patients with symptomatic HF, all participants were required to have reduced left ventricular ejection fraction (LVEF) <45% and low vitamin D status (<20 ng/ml). The investigators tested the hypothesis that 1 year of vitamin D supplementation would improve the primary endpoint of 6-minute walking distance and secondary endpoint of LVEF.

Among the 163 patients who completed the trial, oral vitamin D supplementation effectively raised serum vitamin D concentrations compared with placebo. The primary endpoint didn’t improve in patients randomized to vitamin D compared with placebo, but supplementation did appear to have a favorable effect on LVEF (measured by echocardiography), with an 8% improvement in the active arm. Clinical endpoints, such as mortality or hospitalization, weren’t evaluated.

VINDICATE was the largest study to date to examine this hypothesis in the setting of high use of contemporary guideline-directed medical therapy (>90% on angiotensin-converting enzyme inhibitors and beta-blockers). Unfortunately, the trial had a high rate of attrition, as only 73% of the original cohort were on therapy at the end of the study period. The exact reasons for the drop outs weren’t explained, but they do reduce the power of the trial to detect a benefit of vitamin D therapy.

Although the overall findings are disappointing, the LVEF data alone are encouraging. Other clinical trials have shown that each 5% increase in LVEF is associated with a 28% to 50% reduction in the risk of death or hospitalization for HF.

Regardless, these findings must be viewed as hypothesis-at this time. Unfortunately, existing data still aren’t sufficiently robust for pharmacists to routinely recommend vitamin D supplementation to patients with HF and low serum vitamin D levels. Given the low cost and proven safety of vitamin D supplementation, however, I feel that larger, randomized trials are certainly warranted to further explore possible benefits for patients with HF and a reduced LVEF.

References

• Gupta DK et al. Looking for a brighter future in heart failure: A role for vitamin D supplementation? J Am Coll Cardiol. 2016;67(22):2604-2606.
• Witte KK, Byrom R, Gierula J, et al. Effects of vitamin D on cardiac function in patients with chronic HF: the VINDICATE study. J Am Coll Cardiol. 2016;67:2593-2603.