Effectiveness and Safety of the Direct Oral Anticoagulants in Low-Risk Antiphospholipid Syndrome: A Case Series

Introduction: Thrombotic Antiphospholipid syndrome (TAPS) is an autoimmune condition where venous thromboembolism (VTE) and/or arterial thromboembolism (ATE) occurs in the presence of antiphospholipid antibodies (aPLs). TAPS is traditionally managed with long-term anticoagulation with vitamin K antagonists (VKA).

Over the past decade, direct oral anticoagulants (DOACs) have been increasingly replacing VKAs as the oral anticoagulant of choice given their lower risk of bleeding, fixed dosing, and no requirement for routine monitoring. However, recent evidence has demonstrated inferiority of DOACs compared to VKAs in TAPS patients with high risk (triple positive) aPL profiles or previous arterial events. It remains unclear whether TAPS patients with low risk aPL profiles (single positive), and without previous ATE, can be treated effectively and safely with DOACs.

Objectives: To assess the effectiveness and safety of DOACs at preventing recurrent VTE or ATE in TAPS patients with a low risk aPL profile, and without prior ATE.

Methods: We conducted a retrospective review of all TAPS patients with a low risk aPL profile, without prior ATE, who were anticoagulated with a DOAC at two tertiary care hospitals in Toronto, Canada from January 2010 to July 2020.

All patients with any positive aPL test results were first identified through the laboratory information system. This list was cross referenced with patients seen in specific thrombosis clinics and confirmed through individual electronic chart review. TAPS was defined as persistent (>12 weeks apart) lupus anticoagulant (LA) positivity, anti-cardiolipin titre (ACA) >40 GPL, or anti-2-glycoprotein 1 titre (a2GP1) >40 GPL, with a preceding thrombotic event. Patients were excluded if any of the aPLs were deemed to be simultaneously positive or if there was a history of previous ATE. a2GP1 was not systematically tested in all patients.

Patient outcomes were assessed throughout the duration of anticoagulation with a DOAC. Recurrent VTE included deep vein thrombosis, pulmonary embolism, or VTE of atypical location, and required objective confirmation with appropriate diagnostic imaging. ATE included ischemic stroke, transient ischemic attack (TIA), myocardial infarction, or other systemic arterial embolism. Major bleeding (MB) and clinically relevant non major bleeding (CRNMB) were defined by International Society on Thrombosis and Hemostasis criteria.

Results: 1195 patients were identified with at least one instance of single positive aPL who had been seen in one of the thrombosis clinics. Patients were excluded for the following reasons: 858 for non-persistent aPL positivity, 70 for simultaneous aPL positivity, 20 for a likely false positive LA due to DOAC therapy, 93 due to an absence of preceding VTE, 45 for history of previous ATE, and 59 due to no prior DOAC therapy. After exclusions, 50 patients were included in the analysis, encompassing 157.2 years of patient-follow up.

The study population was comprised of 24 women and 26 men with a mean age of 49.6 (standard deviation (SD) 16.3)years at the start of DOAC therapy (Table 1). The mean duration of DOAC treatment was 37.7 (SD 23.8) months. Fifteen (30%) patients had prior diagnosis of systemic lupus erythematosus (SLE), while 4 (8%) had other systemic autoimmune disease diagnoses. Only 1 patient met criteria for obstetric APS, on the basis of 3 consecutive fetal losses before 10 weeks gestation. None of the patients had documented valvular disease or thrombocytopenia. All patients were treated initially with therapeutic dose rivaroxaban, although 6 (12%) patients were switched to therapeutic dose apixaban due to increased bruising or menorrhagia. Five patients on rivaroxaban and 3 patients on apixaban were switched to a reduced dose DOAC.

No patient had recurrent VTE. One patient had a possible ATE as a TIA, presenting with an episode of loss of sight for 15 minutes while on reduced dose apixaban. None of the patients experienced MB. Two patients experienced CRNMB, both severe menorrhagia, one on therapeutic dose of rivaroxaban and the other patient on reduced dose of rivaroxaban.

Conclusions: In our retrospective case series of 50 patients with TAPS, a low risk aPL profile and no previous ATE, DOACs were effective and safe in the secondary prevention of thrombotic events with no MB. Larger, prospective controlled studies are required to confirm these findings.