Warfarin use and risk of knee replacement

      Purpose: Vitamin K is an essential co-factor in the post-translational gamma-carboxylation of glutamic acid to form gamma-carboxy-glutamic acid (Gla) residues. This confers functionality to vitamin K-dependent Gla proteins including those in bone and cartilage such as matrix Gla protein (MGP) which plays an important role in regulating mineralization. Inadequate vitamin K can lead to under-carboxylation of Gla proteins and therefore dysfunction of those proteins. Vitamin K deficiency and MGP polymorphisms have been associated with osteoarthritis (OA), and a randomized trial of vitamin K supplementation demonstrated trends towards less OA progression. However, studies to date have not evaluated whether vitamin K antagonism with warfarin can be detrimental to OA. We therefore evaluated the relation of warfarin to risk of knee replacement as a reflection of end-stage knee OA.
      Methods: We conducted a nested case-control study using The Health Improvement Network, a general practitioner based electronic medical records database from the UK that is representative of the general population. To minimize confounding by indication, we limited our study sample to adults (aged 40 to 89 years) with atrial fibrillation, as this diagnosis warrants therapy with anticoagulation. To further address confounding by indication, we compared warfarin, a vitamin K antagonist, with direct oral anticoagulants (DOAC), which are not vitamin K antagonists. Because DOACs were first marketed in the UK in 2008, we limited our study to individuals who had been enrolled for at least one year with a general practitioner between the years 2009 and 2018. We excluded individuals with a knee replacement (KR) prior to 2014, end stage renal disease (DOAC contraindicated), other severe co-morbidities that would limit TKR, those with warfarin or DOAC use prior to our study period, and those who used both drugs during study period. We identified cases as those with KR between 2014-2018, with date of KR defined as the index date for cases. Each case was matched to 4 controls by birth year and gender. We assessed warfarin and DOAC use as those who had at least one prescription after study entry and prior to the index date. We assessed the relation of warfarin compared with DOAC use to risk of KR using conditional logistic regression, adjusting for potential confounders.
      Results: We identified 553 with KR (cases) who were age- and gender-matched 4:1 with 2226 controls who met our inclusion criteria (mean age 74, 45% female). Of the 553 with KR, 71% were warfarin users while 29% were DOAC users; in contrast, of the 2226 controls, 61% were warfarin users while 39% were DOAC users. With adjustment for potential confounders, warfarin users had a 1.6 times higher risk of KR than DOAC users (OR 1.61, 95% CI 1.26-2.06) (Table).
      Conclusions: In this nested case-control study, warfarin use, a vitamin K antagonist, was associated with significantly greater risk of KR (an indicator for end-stage knee OA) than DOAC use. This data adds further support to the importance of adequate vitamin K and vitamin K-dependent proteins for preventing and/or limiting progression of OA.