Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation

Abstract

CORRESPONDENCE C alcific aortic stenosis is a common degenerative disease characterized by progressive aortic valve calcification (AVC). 1 Effective medical treatment options to retard the progression of AVC are sparse. 1 Epidemiological data point to vitamin K as a potential protective factor for cardiovascular health, particularly for protection against vascular calcification. 2,3 Matrix Gla-protein (MGP), a potent inhibitor of cardiovascular calcification, requires vitamin K for posttranslational car-boxylation and hence full bioactivity. 4 Thus, vitamin K supplementation might retard the progression of AVC. 1,2 Dephosphorylated undercarboxylated MGP (dp-ucMGP) serves as a circulating marker for vitamin K deficiency. 2,3 We performed a 12-month prospective, single-center, open-label, randomized interventional trial in patients with asymptomatic or mildly symptomatic AVC. Written informed consent was obtained before inclusion in the trial (URL: http://www. clinicaltrials.gov. Unique identifier: NCT00785109; RWTH Aachen Institutional Review Board No. 165/08). Inclusion criterion was a peak flow velocity exceeding 2 m/s. The main exclusion criteria were chronic kidney disease (estimated glomerular filtration rate <60 mL·min −1 ·1.73 m −2), expected valve replacement within the next year, and anticoagulation with vitamin K antagonists. Patients were randomized 1:1 to receive 2 mg phytomenadione (vitamin K 1 , Ka-vit, INFECTOPHARM Arzneimittel CONSILIUM GmbH, Heppenheim, Germany) or matching placebo once daily orally. Patients underwent a baseline and end-of-study cardiac computed tomography (CT) scan for AVC quantification (volume calcification score). All CT examinations were performed on a 128-slice dual-source CT scanner (SOMATOM Definition Flash, Sie-mens, Germany) and were reanalyzed in a blinded fashion by 2 radiologists experienced in cardiac CT. The primary end point was the difference in progression of AVC volume score between vitamin K and placebo. We also assessed changes of dp-ucMGP plasma levels (IDS, Boldon, UK) as a secondary end point. Linear regression models for AVC change with treatment effect and baseline measures were used as independent variables, and 95% confidence intervals for treatment effects were calculated. The trial cohort included 99 patients (82% male; 35% with aortic sclerosis [≤2.5 m/s], 38% with mild aortic stenosis [2.6-2.9 m/s], and 27% with moderate aortic stenosis [3.0-4.0 m/s]; 71% of each group received statins). Seventy-two participants also underwent an end-of-study cardiac CT scan (representing the per-protocol analysis cohort: n=38 vitamin K, n=34 placebo). Twenty-seven patients (12 vitamin K, 15 placebo) dropped out of the study. Reasons for discontinuation were initiation of oral anticoagulant treatment (n=3 placebo, n=4 vitamin K), loss to follow-up, withdrawal of consent (n=6 placebo, n=3 vitamin K), cardiac surgery (n=2 each), death (n=1 each), or other reasons (n=3 placebo, n=2 vitamin K). Over the 12-month period, the AVC volume score progressed by 10.0% in patients in the vitamin K group compared with 22.0% in the placebo group (Table), representing a significant attenuation of AVC progression by vitamin K compared with placebo. Linear