Objectives Vascular stiffness (VS) and vascular calcification (VC) are surrogate markers of vascular health associated with cardiovascular events. Vitamin K-dependent proteins (VKDP) are associated with VS and VC and require vitamin K for activity. We conducted a systematic review and meta-analysis of: (1) the effect of vitamin K supplementation on VS and VC and (2) association of inactive VKDP levels with incident cardiovascular disease and mortality.
Methods Two authors searched MEDLINE and Embase databases and Cochrane and ISRCTN registries for studies of vitamin K clinical trials that measured effects on VC, VS or VKDP and longitudinal studies assessing effect of VKDP on incident CVD or mortality. Random effects meta-analyses were performed.
Results Thirteen controlled clinical trials (n=2162) and 14 longitudinal studies (n=10 726) met prespecified inclusion criteria. Vitamin K supplementation was associated with significant reduction in VC (−9.1% (95% CI −17.7 to −0.5); p=0.04) and VKDP (desphospho-uncarboxylated matrix Gla protein; −44.7% (95% CI −65.1 to −24.3), p<0.0001) and uncarboxylated osteocalcin; −12.0% (95% CI −16.7 to −7.2), p<0.0001) compared with control, with a non-significant improvement in VS. In longitudinal studies with median follow-up of 7.8 (IQR 4.9–11.3) years, VKDP levels were associated with a combined endpoint of CVD or mortality (HR 0.45 (95% CI 0.07 to 0.83), p=0.02).
Conclusions Supplementation with vitamin K significantly reduced VC, but not VS, compared with control. The conclusions drawn are limited by small numbers of studies with substantial heterogeneity. VKDP was associated with combined endpoint of CVD or mortality. Larger clinical trials of effect of vitamin K supplementation to improve VC, VS and long-term cardiovascular health are warranted.
Trial registration number CRD42017060344.
- cardiac risk factors and prevention
- coronary artery disease
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Contributors JSL, MDW, AGJ and PBM designed the research; JSL and FAC conducted the research; JSL and MDW analysed the data; JSL, MDW and PBM wrote the paper; JSL had primary responsibility for final content. All authors read and approved the final manuscript.
Funding JSL is funded by a Kidney Research UK Training Fellowship (TF_013_20161125).
Competing interests MDW and PBM acknowledge project grant funding from British Heart Foundation (PG/14/75/31083) to support the K for Kidneys trial: ISRCTN21444964. The above Kidney Research UK Training Fellowship was awarded to JSL (supervised by PBM) for the ViKTORIES trial: ISRCTN22012044.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional unpublished data available. Data used for the purposes of these analyses are available in previously published articles.