Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

Circulation

Apr 2022

DOI: 10.1161/CIRCULATIONAHA.121.057008

Citations:43

Influential Citations:0

Interventional (Human) Studies

Enhanced Details

Methods

Multicenter randomized, double-blind, placebo-controlled trial at four Danish hospitals. Participants: community-dwelling men aged 65-74 years with aortic valve calcification score ≥300 AU on noncontrast CT; Exclusions: prior heart valve surgery, moderate aortic stenosis (peak aortic jet velocity >3.0 m/s), treatment with vitamin K antagonists, or calcium/phosphate metabolism or coagulation disorders.

Intervention

Daily oral tablet containing 720 µg menaquinone-7 and 25 µg vitamin D for 24 months.

Results

No significant difference in AVC progression over 24 months: MK-7 plus vitamin D changed AVC by 275 AU vs 292 AU in placebo (difference −17 AU; 95% CI −86 to 53; P=0.64). No significant differences in aortic valve area or peak jet velocity; progression of arterial calcification and need for valve surgery or cardiovascular events did not differ. dp-ucMGP decreased with MK-7 plus vitamin D (−212 pmol/L vs 45 pmol/L; P<0.001), indicating improved vitamin K status. The combination was safe and well tolerated. Conclusion: 2 years of MK-7 plus vitamin D does not slow AVC progression in elderly men with AVC ≥300 AU.

Limitations

External validity limited to men aged 65-74 years with AVC >300 AU; 389 randomized from 660 eligible; 333 completed; potential underpower due to smaller-than-planned sample size and possible underdosing or insufficient duration; results may not apply to women.

Abstract

Background: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis. Methods: In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events. Results: From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225–326 AU) and 292 AU (95% CI, 246–338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, –86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, –0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, –0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (–212 pmol/L versus 45 pmol/L; P<0.001). Conclusions: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03243890. show less