Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-center, pilot trial

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.

Association of Vitamin K Status with Arterial Calcification and Stiffness in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort

“…We also found no difference in CAC prevalence or incidence across plasma (dp)ucMGP categories. Our results are generally consistent with the available recent evidence from vitamin K supplementation randomized controlled trials (RCTs), which collectively do not support a protective role for vitamin K supplementation in improving the vascular health of individuals with CKD [ [33] , [34] , [35] ].…”

“…A trial conducted in adults with stage 3b-4 CKD found no effect of 400 μg/d menaquinone-7 (a form of vitamin K2) on arterial stiffness or other measures of vascular health over 1 y [34]. In a recently completed pilot RCT comprising individuals on hemodialysis with a baseline AS of ≥30 AU, phylloquinone supplementation (10 mg thrice weekly) showed no effect on CAC progression over 1 y [ 35 ]. Results of RCTs focused on arterial stiffness were similarly unconvincing [ 33 ].…”

“…In summary, vitamin K status was generally not associated with coronary calcification or arterial stiffness in adults with mild-to-moderate CKD. Moreover, the collective results of the available RCTs do not support a protective role for vitamin K supplementation in improving the vascular health of individuals with CKD [ [33] , [34] , [35] ]. Given the burden of poor vascular health in CKD, alternate therapeutic strategies merit investigation.…”

Accelerated Vascular Aging in Chronic Kidney Disease: The Potential for Novel Therapies

“…125 As underpowered clinical randomized Vitamin K trials have shown divergent results, fully powered randomized trials should be initiated possibly combining vitamin K2 with a phosphate binder. [126][127][128][129] Mitochondrial Dysfunction-When Cells Run Out of Energy…”

Effects of vitamin K supplementation on vascular calcification in chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials

“…In all, the ten RCTs involved 733 patients, including 365 in interventional group and 367 in control groups. Among these studies, six were conducted in hemodialysis patients (13)(14)(15)(16)(17)(18)(19), two were conducted in non-dialysis CKD patients (20, 21), and one was conducted in kidney transplantation recipients (22). All studies were conducted in adult population, except for one study which had been conducted in pediatric population.…”