Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Summary. Background: The characteristics and the clinical course of antiphospholipid syndrome (APS) in high-risk patients that are positive for all three recommended tests that detect the presence of antiphospholipid (aPL) antibodies have not been described. Methods: This retrospective analysis of prospectively collected data examined patients referred to Italian Thrombosis Centers that were diagnosed with definite APS and tested positive for aPL [lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-b2-glycoprotein I (b2GPI) antibodies]. Laboratory data were confirmed in a central reference laboratory. Results: One hundred and sixty patients were enrolled in this cohort study. The qualifying events at diagnosis were venous thromboembolism (76 cases; 47.5%), arterial thromboembolism (69 cases; 43.1%) and pregnancy morbidity (11 cases; 9.7%). The remaining four patients (2.5%) suffered from catastrophic APS. The cumulative incidence of thromboembolic events in the follow-up period was 12.2% (95%CI, 9.6-14.8) after 1 year, 26.1% (95%CI, 22.3-29.9) after 5 years and 44.2% (95%CI, 38.6-49.8) after 10 years. This was significantly higher in those patients not taking oral anticoagulants as compared with those on treatment (HR=2.4 95%CI 1.3-4.1; P < 0.003). Major bleeding associated with oral anticoagulant therapy was low (0.8% patient/years). Ten patients died (seven were cardiovascular deaths). Conclusions: Patients with APS and triple positivity for aPL are at high risk of developing future thromboembolic events. Recurrence remains frequent despite the use of oral anticoagulants, which significantly reduces the risk of thromboembolism.

Persistent antiphospholipid (aPL) antibodies are occasionally found in subjects without prior history of thromboembolic events (TEs), raising the dilemma of whether to initiate or not a primary thromboprophylaxis. A first TE is considered rare in aPL carriers, but previous studies did not consider the aPL profile nor was the test positivity confirmed in a reference laboratory. In this study, 104 subjects with high-risk aPL profile (positive lupus anticoagulant, anticardiolipin, and anti-␤ 2 -glycoprotein I antibodies, triple positivity) confirmed in a reference laboratory, were followed up for a mean of 4.5 years. There were 25 first TEs (5.3% per year): the cumulative incidence after 10 years was 37.1% (95% confidence interval [CI], 19.9%-54.3%). On multivariate analysis, male sex (hazard ratio ‫؍‬ 4.4; 95% CI, 1.5-13.1, P ‫؍‬ .007) and risk factors for venous thromboembolism (hazard ratio ‫؍‬ 3.3; 95% CI, 1.3-8.5, P ‫؍‬ .01) were independent predictors for TEs. Aspirin did not significantly affect the incidence of TE. In conclusion, the occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE. These data can help in the decision to initiate primary thromboprophylaxis in these subjects. (Blood. 2011; 118(17):4714-4718)

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Summary. Background: Determination of lupus anticoagulant (LA), anticardiolipin (aCL) and b2-Glycoprotein 1 (ab2GP1) antibodies is mandatory to classify patients with antiphospholipid syndrome (APS) into risk categories. Objectives: To measure relevant antibodies, considered to be those of the IgG isotype directed towards b2GP1 and particularly those directed to Domain 1 (Dm1) of the molecule. Patients/methods: In this cross-sectional study we measured IgG ab2GP1-Dm1 by a chemiluminescent immunoassay in a group of individuals initially positive for IgG ab2GP1 and classified as triple (LAC+, IgG aCL+, IgG ab2GP1+, n = 32), double (LAC-, IgG aCL+, IgG ab2GP1+, n = 23) or single positive (LA-, IgG aCL-, IgG ab2GP1+, n = 10). Results and conclusion: Geometric mean and standard deviation expressed as chemiluminescent units (CU) in triple, double and single positive groups were 273.0 AE 6.2, 18.2 AE 9.6 and 4.4 AE 2.2, respectively. The geometric mean obtained in 40 healthy subjects was 2.0 AE 2.0. Mean CU values were significantly different among groups and with respect to values found in 40 healthy subjects (P < 0.0001). Positive values of IgG ab2GP1-Dm1 (above 14.2 CU) were found in 45 individuals while 20 individuals (20/65 = 30.8%) positive for IgG ab2GP1 were negative for IgG ab2GPI-Dm1. There was a significant association between positive IgG ab2GP1-Dm1 and thromboembolic events (P = 0.001). Positive and negative values of IgG ab2GP1-Dm1 were consistently confirmed after 12 weeks, with only three low positive values being negative after 12 weeks. In conclusion, IgG ab2GP1-Dm1 seems a robust and reproducible test that in association with the classic tests may be useful in clinical practice in identifying individuals at high risk of developing thromboembolic events.