Inhibiting the progression of arterial calcification with vitamin K in hemodialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease

Authors: HOLDEN, RACHEL - Queen'S University - Canada; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DAY, ANDREW - Kingston General Hospital; CLASE, CATHERINE - McMaster University; ZIMMERMAN, DEBORAH - University Of Ottawa; MOIST, LOUISE - Western University; SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MCCABE, KRISTIN - Queen'S University - Canada; JAMAL, SOPHIE - University Of Toronto; TOBE, SHELDON - University Of Toronto; WEINSTEIN, JORDAN - University Of Toronto; MADHUMATHI, RAO - Tufts University; ADAMS, MICHAEL - Queen'S University - Canada; HEYLAND, DAREN - Queen'S University - Canada

Submitted to: Canadian Journal of Kidney Health and Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/23/2015
Publication Date: 5/1/2015
Citation: Holden, R.M., Booth, S., Day, A.G., Clase, C.M., Zimmerman, D., Moist, L., Shea, K., McCabe, K.M., Jamal, S.A., Tobe, S., Weinstein, J., Madhumathi, R., Adams, M.A., Heyland, D.K. 2015. Inhibiting the progression of arterial calcification with vitamin K in hemodialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease. Canadian Journal of Kidney Health and Disease. 2:17. https://doi.org/10.1186/s40697-015-0053-x.
DOI: https://doi.org/10.1186/s40697-015-0053-x

Interpretive Summary: Cardiovascular disease, which is due, in part, to progressive vascular calcification, is the leading cause of death among patients with end stage kidney disease on dialysis. A role for vitamin K in the prevention of vascular calcification is plausible based on the presence of vitamin K-dependent proteins in vascular tissue, including the matrix gla protein. Evidence from animal models and observational studies supports a role for vitamin K in the prevention of vascular calcification. A large-scale study is needed to investigate the effect of vitamin K supplementation on the progression of vascular calcification in patients with end stage kidney disease, a group at risk for sub-clinical vitamin K deficiency. We plan a prospective, randomized, double-blind, multicenter controlled trial of incident end stage kidney disease patients on hemodialysis in centers within North America. Eligible subjects with a baseline coronary artery calcium score of greater than or equal to 30 Agatston Units will be randomly assigned to either the treatment group (10 mg of vitamin K three times per week) or to the control group (placebo administration three times per week.) The primary endpoint is the progression of coronary artery calcification defined as a greater than 15% increase in coronary artery calcification score over baseline after 12 months. Vitamin K supplementation is a simple, safe, and cost-effective nutritional strategy that can easily be integrated into patient care. If vitamin K reduces the progression of coronary artery calcification, it may lead to decreased morbidity and mortality in men and women with end stage kidney disease.

Technical Abstract: Background: Cardiovascular disease, which is due in part to progressive vascular calcification, is the leading cause of death among patients with end stage kidney disease (ESKD) on dialysis. A role for vitamin K in the prevention of vascular calcification is plausible based on the presence of vitamin K dependent proteins in vascular tissue, including matrix gla protein (MGP). Evidence from animal models and observational studies support a role for vitamin K in the prevention of vascular calcification. A large-scale study is needed to investigate the effect of vitamin K supplementation on the progression of vascular calcification in patients with ESKD, a group at risk for sub-clinical vitamin K deficiency. Methods/Design: We plan a prospective, randomized, double-blind, multicenter controlled trial of incident ESKD patients on hemodialysis in centers within North America. Eligible subjects with a baseline coronary artery calcium score of greater than or equal to 30 Agatston Units, will be randomly assigned to either the treatment group (10 mg of phylloquinone three times per week) or to the control group (placebo administration three times per week). The primary endpoint is the progression of coronary artery calcification defined as a greater than 15% increase in CAC score over baseline after 12 months. Discussion: Vitamin K supplementation is a simple, safe and cost-effective nutritional strategy that can easily be integrated into patient care. If vitamin K reduces the progression of coronary artery calcification it may lead to decreased morbidity and mortality in men and women with ESKD.