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Rivaroxaban (Xarelto) was no match for standard of care in the long-term anticoagulation of patients with antiphospholipid antibody syndrome (APS), a Spanish trial found.

The direct oral anticoagulant (DOAC) led to more arterial, venous, and stroke thrombotic events, with 11.6% recurrent thrombosis over 3 years compared with 6.3% among those randomized to warfarin or other vitamin K antagonists (VKAs, RR 1.83, 95% CI 0.71-4.76; P=0.29 for non-inferiority).

This disadvantage was apparently driven by excesses in arterial thrombotic events and strokes, reported Josefina Cortés-Hernández, MD, PhD, of Vall d'Hebron University Hospital Research Institute in Barcelona, and colleagues in the paper in .

"Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non–statistically significant near doubling of the risk for recurrent thrombosis," the group concluded.

A post hoc analysis suggested an increased risk for recurrent blood clots in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease. But although these are already known risk factors for arterial thrombosis in APS, the subgroup analysis was underpowered, the authors cautioned.

These results support from the European League Against Rheumatism recommending against the use of rivaroxaban in patients with APS and triple positivity, particularly those with previous arterial thromboses, according to Denis Wahl, MD, PhD, and Virginie Dufrost, MD, both of the University of Lorraine and CHRU de Nancy, France, in an .

"Moreover, the European Medicines Agency has issued a regarding a higher thrombotic risk for patients with APS and triple positivity who are receiving DOACs. Thus, the data now available ... suggest that DOACs should not be prescribed for patients with high-risk APS," the editorialists said.

The open-label non-inferiority trial included 190 adults with thrombotic APS. These were individuals with or moderate-to-high levels of IgG anticardiolipin, anti–2-glycoprotein I antibodies, or both.

Trial participants had been recruited in 2013-2014 at six hospitals in Spain. They were subsequently randomized to rivaroxaban (dosed according to renal function) or dose-adjusted VKAs.

Overall, the cohort comprised roughly 64% women. Besides the slightly younger age among rivaroxaban recipients (median age 47 years vs 51 years for VKA), there was also higher prevalence of migraine and livedo racemosa in that arm.

Major bleeding rates were similar between rivaroxaban and VKA recipients (6.3% vs 7.4% as-treated, RR 0.86, 95% CI 0.30-2.46). Odds of mortality were similar as well (5.3% vs 3.2%, RR 1.67, 95% CI 0.41-6.78), with most deaths being cancer-related.

The 97% adherence to rivaroxaban -- by self-reported questionnaires and residual pill counts -- was "adequate," the investigators noted.

"Because no routine coagulation assay exists to monitor , some treatment interruptions may go unnoticed and cause thrombotic recurrences," Wahl and Dufrost pointed out.

Trial investigators acknowledged the limitation that anticoagulation intensity could not be measured in the rivaroxaban group.

The failure of rivaroxaban in this trial may be disappointing given that long-term anticoagulation with warfarin can pose problems of food-drug interactions, bleeding complications, and the need for frequent monitoring, Cortés-Hernández's team suggested.

"Our results are consistent with those of observational studies showing recurrent thrombosis in patients with APS after switching from warfarin to DOACs, as well as with the findings of ," they wrote. "As in our study, a higher rate of thrombotic events was observed in the rivaroxaban groups, all occurring in the arterial circulation."

Reasons for that higher risk might include suboptimal drug concentration and higher anti-Xa activity requirements to prevent arterial events, according to Cortés-Hernández and collaborators.

Then there's the fact that rivaroxaban targets only coagulation factor Xa -- whereas warfarin targets factors II, VII, IX, and X along with proteins S and C, and also has a pharmacokinetically longer half-life.

"One explanation may have been found in a study using a comprehensive thrombin generation assay, which demonstrated that thrombin potential in patients receiving rivaroxaban than those receiving VKAs," suggested Wahl and Dufrost.

For now, it's up in the air whether there is a lower-risk subset of patients with APS who might be eligible for DOAC therapy, they said.

Additional unknowns are whether additional therapy with aspirin or hydroxychloroquine might be effective in APS, and if apixaban (Eliquis) and other DOACs should be considered.