Boston—Using warfarin, a vitamin K drug widely prescribed to prevent blood clots, appears to significantly increase risk of knee and hip replacements in patients with osteoarthritis (OA), according to a study presented at ACR Convergence, the American College of Rheumatology’s annual meeting.
Boston University School of Medicine–led researchers point out that Vitamin K is an essential cofactor in conferring functionality to vitamin K-dependent proteins, including those in bone and cartilage, that play an important role in regulating mineralization.” Low vitamin K can lead to under-carboxylation of Gla proteins and thus their dysfunction,” they write.
The authors further state that vitamin K deficiency has been associated with OA, and past research on vitamin K supplementation demonstrated trends towards less OA progression. Yet little evidence exists on whether vitamin K antagonism with warfarin can be detrimental to OA, leading to this study to evaluate the relation of warfarin to risk of knee and hip replacements as a reflection of end-stage OA.
The nested case-control study used The Health Improvement Network, a general practitioner (GP)–based electronic medical records database from the United Kingdom that is representative of the general population. Researchers said that, to minimize confounding by indication, the study was limited to adults (aged 40-89 years) with atrial fibrillation, a diagnosis that warrants therapy with anticoagulation.
The study also compared warfarin with direct oral anticoagulants (DOACs), which are not vitamin K antagonists. Because DOACs were first marketed in the UK in 2008, the study was limited to patients who had been enrolled for a year or more with a general practitioner between 2009 and 2018. Excluded were patients with knee or hip replacement (KR/HR) prior to 2014, severe comorbidities that would limit surgery, those with warfarin or DOAC use within 1 year prior to the study period, and those who used both drugs during the study period.
Cases involving knee or hip replacements between 2014-2018 were identified, with surgery date being the index date for one. Each case was matched with up to four controls by age and gender. Warfarin and DOAC use were defined as having ≥1 prescription after study entry and within 1 year prior to the index date. Ultimately, 913 cases with KR or HR who were age and gender-matched 4:1 with 3,652 controls (mean age 74, 46% female) were included in the study.
Of the 913 cases, 64.9% were warfarin users while 35.1% were DOAC users. On the other hand, among the controls, 56.3% were warfarin users while 43.6% were DOAC users.
Results indicate that, with adjustment for potential confounders, warfarin users had 1.57 times higher odds of KR or HR than DOAC users (adjusted OR 1.57; 95% CI, 1.30-1.89).
“When matched by practice ID to account for practice variation, we found a slightly diminished but significant association (adjusted OR 1.25; 95% CI, 1.03-1.52),” researchers conclude. “There was increasing risk of KR or HR with duration of warfarin vs. DOAC exposure.”
“We hypothesized that disruption of the functioning of vitamin K-dependent bone and cartilage proteins through vitamin K antagonism may lead to abnormalities in chondrocyte functioning with adverse effects on cartilage health, which in turn can increase the risk of developing or worsening of OA,” explained study coauthor Priyanka Ballal, MD, rheumatology fellow at Boston University Medical Center. “Because direct oral anti-coagulants are alternate options for anticoagulation that do not inhibit vitamin K’s functioning, clarifying this risk of warfarin would give providers and patients valuable information when they consider their choice of anticoagulation in patients with atrial fibrillation.”
The authors emphasize that their data supports the importance of adequate vitamin K in limiting the progression of OA in patients and makes a case for the consideration of using direct oral anticoagulants instead of warfarin when indicated in people with OA or at risk for the disease.
“Our research supports the importance of adequate Vitamin K and dependent proteins for limiting progression of OA,” Dr. Ballal added. “Given these potential adverse effects of warfarin on joint health, our study suggests that direct oral anticoagulants could be considered for managing atrial fibrillation among patients who have OA. The next steps for our group’s research are the design and launch of an adequately powered randomized trial to test the efficacy of vitamin K supplementation for OA outcomes.”
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