Witte KK, Byrom R, Gierula J, et al.
J Am Coll Cardiol 2016;67:2593–603

Background

Despite the substantial improvements in the prognosis of chronic heart failure (HF) during the last 2 decades, HF mortality is still high, since about half of HF patients die within 5 years of diagnosis [1]. Approximately 90% of chronic HF patients are affected by vitamin D deficiency, which has been associated with the progression of chronic HF [2,3]. Vitamin D, a steroid hormone, exerts several pleiotropic effects that may impact on HF severity, and yet, studies examining vitamin D supplementation in chronic HF led to conflicting results [4-9].
In the VINDICATE study, the safety and efficacy of long-term, high-dose  vitamin D3 (cholecalciferol, 4,000 IU [100 µg] daily) supplementation on submaximal exercise capacity and cardiac function was evaluated, in 229 chronic HF patients with left ventricular systolic dysfunction and vitamin D deficiency (vitamin D <50 nmol/l [<20 ng/ml]).

Main results

Out of the 229 patients enrolled in the study, 223 were randomised, and only 163 completed the study. There were no important clinical differences at baseline between patients completing the study and those who dropped out. Eighty-three patients were allocated to the placebo arm versus 80 to the vitamin D supplement arm.

Median concentrations of serum 25 (OH) vitamin D3, 25(OH)D₃, at 12-months post-randomisation (P < 0.0001):

• placebo arm: 24.5 nmol/l; range: 10.0 - 81.8 nmol/l [9.8 ng/ml; range: 4 - 32.7 ng/ml]
• vitamin D arm: 115 nmol/l; range: 17.8 - 193 nmol/l [46 ng/ml; range: 7.1 - 77.2 ng/ml]

After 12 months of high-dose vitamin D3 supplementation, the 6-min walk test was not improved or preserved. Regarding cardiac function, structure, and volumes, changes in the placebo arm versus the vitamin D arm were as follows:

• LVEF: placebo arm +1.36% (95% CI: -0.38 to 3.11%) versus vitamin D arm +7.65% (95% CI: 5.21 to 10.09%), P < 0.0001
• LV end diastolic diameter: placebo arm 0.08 mm (95% CI: -1.25 to 1.10 mm) versus vitamin D arm -2.45 mm (95% CI: -3.70 to -1.21 mm), P = 0.002
• LV end systolic diameter: placebo arm -0.99 mm (95% CI: -2.31 to 0.33 mm) versus vitamin D arm -2.72 mm (95% CI: -4.52 to -0.92 mm), P = 0.043
• LV end diastolic volume: placebo arm -3.83 ml (95% CI: -13.36 to 5.70 ml) versus vitamin D arm -16.47 ml (95% CI: -25.71 to -7.22 ml), P = 0.04
• LV end systolic volume: placebo arm -8.49 ml (95% CI: -17.98 to 1.01 ml) versus vitamin D arm -18.77 ml (95% CI: -25.96 to 9.59 ml), P = 0.041

Moreover, a dose-response relationship was observed between increase in vitamin D levels and:

• increase in LVEF (coefficient 0.04; P = 0.023)
• decrease in LV end diastolic volume (coefficient -0.02; P = 0.035)

Conclusion

In chronic HF patients with left ventricular systolic dysfunction and vitamin D deficiency, high-dose vitamin D3 supplementation is safe, well tolerated, and associated with a favourable effect on cardiac function and structure, although no improvement of the 6-min walk test was observed.

Editorial comment [10]

In their editorial comment, Gupta and Wang comment on two important aspects of the Witte et al study: a) the fact that no improvement of the 6-minute walk test was observed in the vitamin D arm is attributed to high variability that decreased the power of the study to the point where the detection of clinically relevant differences was not possible any longer and b) the high drop-out of the study that is not fully explained, although participants who dropped out had similar characteristics to those who completed the study. ‘The study by Witte et al. is an important contribution to a field in great need for robust randomized trial data.’ And they conclude: ‘How do we interpret the significant secondary endpoint result with LVEF? In light (no pun intended) of the previous experimental data showing beneficial effects of vitamin D on cardiac structure and function, the clinical finding of improved LVEF is intriguing. It is worth noting that the 8% increase in LVEF seen in VINDICATE is in the range of improvement observed with much more complex interventions, such as cardiac resynchronization therapy in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy).’ (…..) ‘Given the low cost and safety of vitamin D supplementation, we believe that the question of whether vitamin D benefits heart failure patients should be tested in larger randomized trials.’ (…..) ‘Another trial with an intermediate endpoint is unlikely to change how clinicians approach the common scenario of a heart failure patient with vitamin D deficiency. In contrast, a definitive trial on this topic would have substantial implications for both patient care and public health.‘

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