Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis.

Abstract

Direct oral anticoagulants (DOACs) are widely used for secondary prevention of venous thromboembolism (VTE) but their clinical efficacy and safety are not established in Antiphospholipid Syndrome (APS) patients. There is only one randomized controlled trial published while others are still ongoing. Many non-randomized studies have been published in this field with conflicting opinions. We conducted a systematic review using MEDLINE, EMBASE and Cochrane databases from 2000 until March 2018 regarding APS patients treated with DOACs. We performed a patient-level data meta-analysis to a) estimate the prevalence of recurrent thrombosis in APS patients treated with DOACs in the literature, and b) identify variables associated with recurrent thrombosis. We identified 47 studies corresponding to 447 APS patients treated with DOACs. Three commercially available DOACs were analyzed: rivaroxaban (n = 290), dabigatran etexilate (n = 144) and apixaban (n = 13). A total of 73 out of 447 patients (16%) experienced a recurrent thrombosis while on DOACs with a mean duration until thrombosis of 12.5 months. Rates of recurrent thromboses were 16.9% and 15% in APS patients receiving either anti-Xa inhibitors or dabigatran respectively. Triple positivity (positivity for all three antiphospholipid antibodies) was associated with a four-fold increased risk of recurrent thrombosis (56% vs 23%; OR = 4.3 [95%CI; 2.3-7.7], p < 0.0001) as well as a higher number of clinical criteria for APS classification. In patients treated with anti-Xa inhibitors, history of arterial thrombosis was associated with a higher risk of recurrent thrombosis (32% vs 14%; OR = 2.8 [95%CI; 1.4-5.7], p = 0.006). In conclusion, DOACs are not effective in all APS patients and should not be used routinely in these patients. Randomized controlled trials assessing clinical efficacy and safety as primary endpoints are underway. In the meantime, a registry of APS patients on DOACs could be proposed to establish in which APS subgroups DOACs would be a safe alternative to warfarin.