Comparative Analysis of Direct Oral Anticoagulants and Vitamin K Antagonists in Antiphospholipid Syndrome Patients
Authors: Elsebaie Maha AT , Wickham Zoe Alexandra , Debragga Stephanie , Li Juan , Gaddh Manila 
Published: November 2021

Abstract
Introduction
Antiphospholipid syndrome (APS) is a major acquired thrombophilia in which vascular thrombosis (venous or arterial) and/or pregnancy losses occur. Despite the use of vitamin K antagonists (VKAs), the annual risk for recurrent thrombosis among APS patients ranges between 2-5% (Crowther et al. NEJM 2003). The evidence for direct oral anticoagulants (DOAC) use in APS patients is still lacking. Therefore, we conducted a retrospective cohort study to explore the efficacy and safety of DOACs vs. VKAs in this patient population.
Methods
The electronic medical records at Emory University Hospitals were queried for patients ≥18 years old with APS diagnosis, according to the Sydney international census criteria (Miyakis et al. JTH 2006). Included patients must have experienced acute thrombosis between 01/01/2012 and 12/31/2018 and started anticoagulation therapy with DOACs or VKAs. We reviewed patient charts from the index thrombosis date till the end of the study period (12/31/2019). Clinical endpoints were: recurrent vascular thrombosis, clinically relevant bleeding (CRB), which included major and non-major bleeding events as defined by the ISTH society, and composite outcome of thrombosis and bleeding (Kaatz et al. JTH 2015). Patients presenting with pregnancy complications only during the identification period were excluded.
Results
A total of 153 patients with confirmed APS diagnosis were included in the study. Mean age was 51 (range, 18-79 y.o.). 94 patients (61.4%) were females and 80 patients (52.3%) were white. The most common sites of index thrombosis were pulmonary embolism (N=62, 40.5%), proximal lower extremity deep venous thrombosis (N=49, 32%), and stroke/TIA (N=29, 19%). The majority of patients had a single positive antiphospholipid antibody (aPL) (N=83, 54.2%). 35 (22.9%) had double positive and 24 (15.7%) had triple positive disease.
Following index thrombosis, 75 patients started DOAC, whereas 72 started warfarin. Six patients started subcutaneous heparin for a short duration before starting an oral form of anticoagulation. Of those on DOAC, 50 started rivaroxaban while 22 started apixaban. After a mean of 19.8 months (range, 0.68 - 69.8) from the index thrombosis, 62 patients (40.5%) switched to a different class of anticoagulation. The most common reasons for switching therapy were recurrent thrombosis (N=16, 25.8%), followed by patient preference (N=13, 20.9%), side effects including bleeding (N=9, 14.5%), and other reasons, such as confirmed APS diagnosis or renal insufficiency (N=12, 19.3%).
We found no statistically significant differences in risk of recurrent thrombosis or CRB events among patients who were started on DOAC vs. VKAs (Figure). The number of arterial thrombosis events was minimal and similar in both treatment groups: N=3 in DOAC group vs. N=5 in the VKA group. Patients treated with rivaroxaban had a similar risk of recurrent thrombosis (log rank, p-value=0.629) and CRB events (log rank, p-value=0.631) compared to those treated with apixaban. The risk of recurrent thrombosis was not affected by degree of aPL positivity or previous history of arterial thrombosis in multivariate models (HR 0.791, 95% CI 0.357 - 1.751) (Table).
Discussion and Conclusion
Our experience suggests that DOACs -particularly rivaroxaban / apixaban- could be an effective and safe alternative to warfarin in APS patients. We realize that patients with triple aPL positivity constitute a special population with a substantial risk of arterial and venous thrombosis. Given the retrospective nature of our data and that triple aPL positive patients compromised only 15% of our patient population, we conclude that the use of DOACs in these high risk patients remains uncertain. Prospective and large-scale multicenter studies are highly encouraged to explore DOAC use in APS patients with various background profiles. We build on our current experience by starting a multicenter collaboration that will facilitate meaningful subgroup comparisons in APS patients.
Figure 1 Figure 1.

Disclosures
Gaddh: Agios: Consultancy, Other: Advisory board.