Cindy Boer

Vitamin K Antagonist Anticoagulants and Osteoarthritis | 143 3.2 Oral VKAs, which includes acenocoumarol and warfarin, were the only oral an- ticoagulants available for decades[31]. New oral anticoagulant drugs developed over the past decade target thrombin (IIa) or factor X (Xa) instead of vitamin K, known as non-vitamin K inhibiting anticoagulants (NOACs) or direct oral anticoagulants (DOACs). Recent years have seen a rise in the use of NOACs[13], which have an improved effica- cy-to-safety ratio over VKAs. Additionally, they do not need routine coagulation moni- toring and have fewer food and drug interactions compared to VKAs; however NOACs are more costly and difficult to reverse[32-34]. Nonetheless, VKAs continue to be com- monly prescribed, and are the only indicated anticoagulant class for certain indications (e.g., antiphospholipid antibody syndrome, mechanical heart valves). With aging of the population, the number of people with OA and requiring anti-coagulation medication will continue to rise. Given our findings of increased risk of OA incidence and progres- sion with VKA and the lack of effective treatment options for OA, it may be reasonable to consider NOACs over VKAs for medical indications in which NOACs can be used. This may be particularly the case for those who are carriers of the MGP risk allele and/or the VKORC1 BB-haplotype, an estimated ~30% of individuals of European ancestry. The strengths of our study include the robust underlying biological hypothesis, large sample size and high quality prospectively collected data. However, some limita- tions of our study should be acknowledged. First, while we found similar results in RS-I and RS-II, analyses in other independent cohorts are warranted, specifically since RSII has a much smaller sample size and number of acenocoumarol users compared to RSI. Also replication in non-Central European (CEU) ancestry based cohorts is warranted. Second, the association we noted in this study may be due to a shared disease pathol- ogy between OA and VKA indications[35, 36]. We attempted to address this issue by adjusting for cardiovascular disease risk factors. However, this possible confounding by indication bias, need to be addressed more directly, by examining direct (new) oral anticoagulants (DOAC/NOAC) users as a comparator group, as these oral anticoagulants do not inhibit the vitamin K-cycle. Unfortunately, our study population contains too few DOAC/NOAC users for such an analysis (n=9). Last, as with all observational studies, we cannot rule out residual confounding. In summary, we found an increased risk of OA progression in users of the VKA acenocoumarol, which was further increased in VKORC1 BB-haplotype and MGP risk allele carriers. These findings are consistent with the known biology of MGP and vita- min K, and are in keeping with prior studies of vitamin K in OA. Taken together, these studies, including the current one, highlight the importance of vitamin K and vitamin K dependent Gla-proteins, including MGP, in the pathogenesis of OA. Given that there are