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.

Patients with an abnormal D-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. The optimal course of anticoagulation in patients with a normal D-dimer level has not been clearly established. (ClinicalTrials.gov number, NCT00264277 [ClinicalTrials.gov].).

Summary.  Background: The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high‐intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0–4.0) vs. moderate (INR 2.0–3.0) intensities of anticoagulation failed to confirm this assumption. Methods: We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high‐intensity warfarin (INR range 3.0–4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0–3.0 in 52 patients or aspirin alone, 100 mg day−1 in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. Results: The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow‐up was 3.2 (SD 0.6) in the high‐intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high‐intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49–7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high‐intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92–5.15). Conclusions: High‐intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.

Introduction: D-dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE). Methods: Commercial D-dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10. Results: In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age-adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event. Conclusion:The results confirm the usefulness of the cutoff levels used in DULCIS.