Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (The iPACK-HD Study): A randomized, placebo-controlled multi-centre, pilot trial

Authors: HOLDEN, RACHEL - Queen'S University - Canada; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ZIMMERMAN, DEBORAH - University Of Ottawa; MOIST, LOUISE - Western University; NORMAN, PATRICK - Kingston Health Sciences Centre; DAY, ANDREW - Kingston Health Sciences Centre; MENARD, ALEX - Queen'S University - Canada; FU, XUEYAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BABIOLAKIS, CORINNE - Queen'S University - Canada; NOLAN, ROBERT - Queen'S University - Canada; TURNER, MANDY - Queen'S University - Canada; WARD, EMILIE - Queen'S University - Canada; KAUFMANN, MARTIN - Queen'S University - Canada; ADAMS, MICHAEL - Queen'S University - Canada; HEYLAND, DAREN - Queen'S University - Canada

Submitted to: Nephrology Dialysis Transplantation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/26/2022
Publication Date: 5/31/2022
Citation: Holden, R.M., Booth, S.L., Zimmerman, D., Moist, L., Norman, P., Day, A.G., Menard, A., Fu, X., Shea, K., Babiolakis, C.S., Nolan, R., Turner, M.E., Ward, E., Kaufmann, M., Adams, M.A., Heyland, D.K. 2022. Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (The iPACK-HD Study): A randomized, placebo-controlled multi-centre, pilot trial. Nephrology Dialysis Transplantation. https://doi.org/10.1093/ndt/gfac191.
DOI: https://doi.org/10.1093/ndt/gfac191

Interpretive Summary: Vitamin K activates a protein that is a key inhibitor of vascular calcification, which can be predictive of heart disease risk. Patients with end stage kidney disease have both a high risk for vascular calcification and a high prevalence of sub-clinical vitamin K deficiency. This has led to the hypothesis that patients with end stage kidney disease may benefit from vitamin K supplementation. To establish the feasibility of conducting a large scale international clinical trial to test this hypothesis, we conducted a pilot trial in patients with end stage renal disease and vascular calcification to establish recruitment rate and adherence overall to the study protocol. We demonstrated that vitamin K supplements in this population improves vitamin K status and that a fully powered randomized trial may be feasible in this patient population.

Technical Abstract: Background: Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end stage kidney disease. Methods: A parallel randomized placebo-controlled pilot trial designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) >= 30 Agatston units. (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion, and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest. Results: Eighty-six patients with a CAC score >= 30 Agatston units were randomized to either 10 mg of phylloquinone or matching placebo three times per week. Sixty-nine participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of >= 4.17 and >= 90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared to placebo. There was no difference in absolute or relative progression of coronary artery calcification between groups. Conclusion: We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.