Response: vitamin K supplementation during oral anticoagulation: no real cause for concern

We are familiar with the concept that oral anticoagulants, by inhibiting the recycling of vitamin K epoxide into its quinone form, might interfere with the functioning of glutamate-containing proteins not associated with hemostasis, in particular matrix Gla-protein, the potent inhibitor of soft tissue calcification, and osteocalcin, promoter of bone formation. The use of coumarins has increased rapidly in the last 15 years following the first publication that anticoagulation therapy is beneficial for thromboembolic prophylaxis in patients with atrial fibrillation.¹ Long-term use of coumarins, in what are now large patient populations, has not firmly established a clinically significant association between therapy and risk of arterial calcification. Work in young rats has established that menaquinone (vitamin K₂), but not phylloquinone (vitamin K₁), has a protective effect against warfarin-induced arterial calcification, perhaps due to the preferential absorption of vitamin K₂ by arterial vessel walls or its more efficient use by carboxylase enzymes.²  However, warfarin doses used in the rat model greatly exceed those received by human subjects on long-term anticoagulant therapy. We hold the view that the potential benefits, in terms of reducing bleeding risk (the consistently reported main adverse effect of oral anticoagulants), which we noted in response to supplementation with vitamin K1,³  outweigh the hypothetical risk of vascular calcification associated with the incremental rise (16% in our study) in warfarin dose.

While the absence of reports of long-term adverse effects in terms of clinically relevant harm from cardiovascular calcification in anticoagulated patients is reassuring, indirect evidence such as that menaquinone is inversely associated with severe aortic calcification as measured by lumbar spine x-ray in asymptomatic individuals,⁴  and the reported association between aortic valve calcification and oral anticoagulant (OA) therapy⁵  (although explainable as a marker of diseases for which treatment with OACs was commenced rather than a response to warfarin), merits further study. Any such investigation, however, will require a robustly designed trial (in terms of power and randomization and with relevant clinical outcomes in terms of coronary artery events, for example) to test the hypothesis that vitamin K₂, through its longer half-life and greater arterial accumulation, has a greater benefit-risk ratio compared with K₁.

The theoretical concerns, while worthy of exploration, should not discourage use of vitamin K₁, in the meantime, to improve safety of anticoagulation in the unstable patient, or discourage further exploration of its role in anticoagulation population in general, where intraindividual variability in response makes regular anticoagulation monitoring a necessity.