Direct Oral Anticoagulants in Antiphospholipid Syndrome: Too Early or Too Late?

Antiphospholipid antibody syndrome (APS) is defined by the association of clinical manifestations (thrombosis or obstetric morbidity) and persistently positive results from laboratory tests for antiphospholipid antibodies: lupus anticoagulants, anticardiolipin, or anti2-glycoprotein I antibodies (1). Most of the recent recommendations for managing patients with APS and previous thrombotic events suggest that long-term anticoagulation with vitamin K antagonists (VKAs), preferably warfarin, should be the standard of care (2). Direct oral anticoagulants (DOACs) have been evaluated and approved during the past decade, providing a novel approach to oral anticoagulation more than 50 years after the introduction of warfarin. Rivaroxaban is an oral, direct factor Xa inhibitor prescribed with a fixed-dose regimen for treating acute venous thromboembolism (VTE) and for long-term therapy, without the need for laboratory monitoring (3). Noninferiority studies comparing rivaroxaban with enoxaparin followed by a VKA have concluded that rivaroxaban is noninferior in terms of preventing recurrent VTE in the general population. Rivaroxaban is also licensed for stroke prevention in patients with atrial fibrillation. In their study, Ordi-Ros and colleagues (4) report the results of their randomized trial comparing efficacy and safety between a fixed dose of rivaroxaban and dose-adjusted VKAs for secondary prophylaxis in the setting of thrombotic APS. To this purpose, the authors included 190 adults (aged 18 to 75 years) with thrombotic APS, the largest sample included in such a trial to date. The authors could not demonstrate noninferiority of rivaroxaban to dose-adjusted VKAs for secondary prevention of thrombosis. Among all randomly assigned patients in the intention-to-treat analysis, primary events occurred in 12 (12.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group. Recurrent events in the rivaroxaban group were mainly arterial, with a high rate of stroke; catastrophic APS developed in 1 patient. Most patients with arterial events in the rivaroxaban group had previous arterial events. Characteristics of patients included in this study (4) indicated a high risk for thrombosis: about 90% of patients in both groups had a high global antiphospholipid score, and 60% had triple positivity of laboratory test results (lupus anticoagulants together with anticardiolipin and anti2-glycoprotein I antibodies), which also confers a high thrombotic risk (2). The results of this trial are in line with those from a previous, prematurely terminated study that compared rivaroxaban with warfarin in thrombotic APS and included only patients with triple positivity of laboratory test results (5). Of interest, the vast majority of recurrent events in both studies were arterial (stroke or myocardial infarction). Both studies failed to demonstrate noninferiority of rivaroxaban to dose-adjusted VKAs and showed a greater proportion of arterial events in the rivaroxaban patient groups. Reasons for rivaroxaban's failure to demonstrate noninferiority in APS still need to be investigated. One explanation may have been found in a study using a comprehensive thrombin generation assay (6), which demonstrated that thrombin potential was much higher in patients receiving rivaroxaban than those receiving VKAs. Some might suggest that this difference may be the result of inhibition of several coagulation factors by VKAs compared with only 1 target for rivaroxaban, but this hypothesis remains to be confirmed. An important issue is patient adherence to treatment. Because no routine coagulation assay exists to monitor rivaroxaban use, some treatment interruptions may go unnoticed and cause thrombotic recurrences. Should other DOAC treatment strategies be considered? Apixaban, another factor Xa inhibitor, has been used in VTE in the general population, and a reduced dose has been shown to be an effective and safe alternative to a conventional regimen for long-term secondary prophylaxis (7). However, this reduced-dose approach was not successful in APS, and the investigators of the ASTRO-APS (Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome) trial (8) had to modify the apixaban regimen to a full dose. Although no formal randomized trial has been done with the thrombin inhibitor dabigatran versus warfarin in APS, data from several trials comparing dabigatran with warfarin could be retrieved. From these data, an indirect comparison of patients receiving either drug could not demonstrate a clear difference in recurrence rates, but whether the patients in all treatment groups had similar risk profiles is unclear (9). A systematic review of individual patient data indicated a higher recurrence rate among patients with previous arterial thrombosis and those with triple positivity who were receiving any DOAC (10). Guidelines proposed under the auspices of the European League Against Rheumatism (2) recommend against the use of rivaroxaban in patients with APS and triple positivity, although this recommendation is based on the only study available when the guidelines were developed (5). The results of this new randomized trial (4) support these guidelines, particularly in patients with previous arterial thromboses. Moreover, the European Medicines Agency has issued a pharmacovigilance warning regarding a higher thrombotic risk for patients with APS and triple positivity who are receiving DOACs (www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-8-11-april-2019-prac-meeting_en.pdf). Thus, the data now available, including those from Ordi-Ros and colleagues (4), suggest that DOACs should not be prescribed for patients with high-risk APS. Future research is needed to determine whether there is a lower-risk subset of patients with APS who might be eligible for DOAC therapy. Important indications of such patient profiles might be obtained through registries, and the efficacy and safety of these drugs must be confirmed in carefully designed and conducted randomized controlled trials.