Short summary

Aortic stenosis is a common heart valve disease and due to the growing elderly population the prevalence is increasing. The disease is progressive with increasing calcification of the valve cusps. A few attempts with medical preventive treatment have failed, thus presently the only effective treatment of aortic stenosis is surgery. This study will examine the effect of menaquinone-7 (MK-7) supplementation on progression of aortic valve calcification. We hypothesize that MK-7 supplementation will slow down the calcification process.

Rationale

Background:

Aortic stenosis is a common heart valve disease and due to the growing elderly population the prevalence is increasing. The disease is progressive with increasing calcification of the valve cusps. A few attempts with medical preventive treatment have failed, thus presently the only effective treatment of aortic stenosis is surgery. This study will examine the effect of menaquinone-7 (MK-7) supplementation on progression of aortic valve calcification (AVC). We hypothesize that MK-7 supplementation will slow down the calcification process.

Method:

Design: Double-blind, randomized, placebo-controlled study. 

Participants: 400 men aged 65-74 years with severe AVC, but without stenosis. Exclusion criteria are treatment with vitamin K antagonist or coagulation disorders.

Intervention: Treatment with MK-7 (720 µg/day) supplemented by the recommended daily dose of vitamin D (25 µg/day) or placebo treatment (no active treatment) for two years.

Outcome: Difference in AVC score from baseline to follow-up at two years.

Sample size: A reduction in AVC progression by half is expected. To prove this, we need to study 200 experimental subjects and 200 control subjects with probability of a type 1 error=5% and type II error=80%.

Randomization: Participants will be randomized 1:1.

Blinding: The intervention and placebo tablets are alike, and the participants and data collectors are kept blinded during the study.

Statistical methods: Intention-to-treat principle for all analyses.

Safety and ethics: There are no reported adverse effects associated with the use of MK-7. The protocol is approved by the Regional Scientific Ethical Committee for Southern Denmark and the Data Protection Agency. Vitamin K is a dietary supplement, and accordingly license from the Danish Medicines Agency is not needed. ClinicalTrials.gov Identifier: NCT03243890

Discussion:

If positive effects are shown a new treatment options may be available for valve calcification. The result of this study will be expected at in 2021.

Description of the cohort

Men aged 65-74 years with substantial aortic valve calcifications. 

Data and biological material

Medical interview

Blood measurements: Creatinine, Natrium, Potassium, Calcium, Magnesium, Albumin, Phosphate, alkaline phosphatase, bone specific alkaline phosphatase, Parathyroid Hormone, Vitamin D and INR

Imaging database including: a contrast and non-contrast cardiac CT scan and a non-contrast CT scanning proximal from the mandibular bone and distally to the proximal third of the femur.

Echocardiography.

Biological material including blood samples is stored.

Collaborating researchers and departments

Department of Cardiology, Odense University Hospital

• Professor Axel Diederichsen
• Professor Jacob Eifer Møller

Department of Cardiothoracic and Vascular Surgery, Odense University Hospital

• Professor Jes Lindholt
• MD Niels Erik Frandsen

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

• Professor Lars Melholt Rasmussen

Department of Cardiology, OUH, Svendborg Hospital

• Associated professor Jess Lambrechtsen

Søren Auscher

Department of Cardiology, Vejle Hospital

• Susanne Hosbond

Dilek Hunerel Alan

Department of Cardiology, Silkeborg Hospital

• Grazina Urbonaviciene
• Søren Warberg Becker

Publications associated with the project

The effects of Menaquinone-7 supplementation in patients with aortic valves calcification: study protocol for a randomized controlled trial, BMJ Open. 2018. In print