No Benefit, but Excess Toxicity, With Rivaroxaban for Patients With High-Risk Antiphospholipid Syndrome

Rivaroxaban and other direct oral anticoagulants are used as an alternative to warfarin for the prevention of thromboembolism, but data do not support routine use of rivaroxaban for patients with antiphospholipid syndrome (APS). In an article published in Blood, investigators examined the safety and efficacy of rivaroxaban in a population of patients with APS who are at high risk of thrombotic events, reporting that the agent showed no benefit, but excess risk, over warfarin.

“APS is an acquired autoimmune disease characterized by the association of thromboembolic events or pregnancy morbidity [with] the presence of antiphospholipid antibodies,” explained the authors, led by Vittorio Pengo, MD, of the University of Padua in Italy.

This prospective, randomized, phase III trial included 120 adult patients with high-risk, “triplepositive” APS, who tested positive for the presence of all three antibodies defining an APS diagnosis (lupus anticoagulant, anti-cardiolipin, and anti-ß2- glycoprotein I) and, thus, “are at highest risk of both a first thrombotic event and of a higher rate of recurrence despite antithrombotic treatment,” the researchers noted.

Following complete blood count measurements, renal and liver function assessments, and standard coagulation tests at the screening visit, participants with a creatinine clearance (CrCl) of >50 ml/min were randomized to either once-daily rivaroxaban at a dose of 20 mg (n=57) or warfarin with an international normalized ratio (INR) target of 2.5 (n=61). Patients with a CrCl of 30 to 50 ml/min received once-daily rivaroxaban at a dose of 15 mg (n=2).

Baseline characteristics were similar between the rivaroxaban and warfarin groups (median age = 46.5 and 46.1 years; median platelet counts = 214.9×109/L and 209.3×109/L, respectively; ranges not reported). Eleven patients in the rivaroxaban group (19%) and 14 in the warfarin group (23%) had an arterial thrombotic event prior to enrollment.

Follow-up visits occurred at one month and three months following randomization, and at six-month intervals thereafter. The primary outcome was composed of the cumulative incidence of the following:

  • thromboembolic adverse events
  • major bleeding
  • vascular death

Trial enrollment began on November 2, 2014, and the study was terminated prematurely because of an excess of events among rivaroxaban-treated patients. At that point, all patients discontinued the study drug and switched to a non-vitamin K antagonist.

The mean follow-up period in the “as-treated” cohort (which excluded 9 rivaroxaban-treated and 3 warfarin-treated patients who discontinued before an endpoint event was recorded) was 569 days, and 611 days in the entire intention-to-treat (ITT) cohort.

Overall, 13 events were reported during followup in the as-treated population, and the composite primary outcome of thromboembolic events, major bleeding, and vascular death occurred in 11 patients in the rivaroxaban group and two patients in the warfarin group. The risk of composite endpoint was nearly seven times greater in the rivaroxaban group, the authors reported (hazard ratio [HR] = 6.7; 95% CI 1.5-30.5; p=0.01).

A similar increased risk of primary outcome was observed in the ITT analysis (TABLE). “Thromboembolic events, all in the arterial circulation, mainly drove the unbalance in the cumulative primary endpoint,” the authors wrote. “Thus, rivaroxaban apparently does not protect high-risk patients from arterial events.”

Efficacy and Safety Outcomes

Rivaroxaban also was associated with a greater incidence of other adverse events, including four patients with ischemic stroke (IS; 7%) and three patients with myocardial infarction (MI; 5%). No patients in the warfarin group experienced either IS or MI.

No significant differences were observed between the two groups in the number of major bleeding cases (4 vs. 2, respectively; HR=2.5; 95% CI 0.5-13.6; p=0.03). In five of six bleeding events, the episode was associated with predisposing factors, including uterine fibroid, anal fissure, Crohn disease, and thrombocytopenia, the researchers noted.

“Based on our data, and the absence of [other] data, rivaroxaban and the other novel oral anticoagulants should not be used in thrombotic high-risk APS patients,” Dr. Pengo told ASH Clinical News. “The results of our trial should raise the awareness among health-care personnel about the lack of efficacy of rivaroxaban in [patients with] high-risk, triple-positive APS and may be relevant for the other trials testing direct anticoagulants in this setting.”

The study’s findings are limited by the trial’s premature discontinuation, and, the authors noted, these results cannot be translated to people without a “triple-positive” APS. “At present, the one therapeutic strategy in patients with a laboratory profile different from that of this study should be considered on a case-by-case basis, taking into account the presence of additional risk factors for venous and arterial thrombosis, the nature of venous thromboembolism (provoked or unprovoked), and the risk of bleeding,” they concluded.

The authors reported no conflicts of interest.


Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 July 12. [Epub ahead of print]

“Some patients with APS are difficult to manage with warfarin because their lupus inhibitor interferes with INR measurements. This can make warfarin ineffective, increasing the risk of bleeding or thrombosis. In these situations, clinicians consider using direct oral anticoagulants, but we don’t have clinical trial results yet that support the use of rivaroxaban or other agents for APS treatment, so informed discussion with patients is needed if this is performed. Given these findings, I would advise an addon, moderate-intensity statin if a direct oral anticoagulant was chosen for patients with non–triple-positive APS who have a 10-year atherosclerotic cardiovascular disease risk of ≥7.5 percent, or an even lower threshold. Hematologists should also consider hydroxychloroquine, an add-on therapy to anticoagulation that is directed at the autoimmune component, as a treatment option for patients with APS.”

Mary Cushman, MD, MSc
The University of Vermont Medical Center
Burlington, VT