Rivaroxaban Falls Flat in Antiphospholipid Antibody Syndrome

Rivaroxaban does not seem to be an effective alternative to vitamin K antagonists (VKAs) in patients with antiphospholipid antibody syndrome (APS), an autoimmune disorder, with randomized results showing that the direct oral anticoagulant (DOAC) failed to meet the bar for noninferiority in terms of new thrombotic events.

After nearly 3 years of follow-up, in fact, recurrent thrombosis was numerically—but not significantly—more frequent in the rivaroxaban group (11.6% vs 6.3%), a finding also seen in a prior trial, researchers report.

“This has been a surprise to everybody working in antiphospholipid syndrome actually, because initially everybody designing the studies thought the efficacy would be similar and this could be a benefit for patients,” Josefina Cortés-Hernández, MD, PhD (Vall d’Hebron Research Institute, Barcelona, Spain), senior author of this new study, told TCTMD. She added that “for us, it has been a great disappointment.”

The study, with lead author Josep Ordi-Ros, MD, PhD (Vall d’Hebron Research Institute), was published online October 14, 2019, ahead of print in the Annals of Internal Medicine.

Refining Anticoagulation in APS

APS is “an acquired thrombophilic disorder in which vascular thrombosis (venous or arterial) and pregnancy losses may occur in the presence of persistent antiphospholipid antibodies,” the authors explain. Chronic anticoagulation with VKAs is the standard treatment to prevent thrombotic events.

DOAC therapy is an attractive and often preferred alternative to VKAs in other medical settings owing to greater ease of use, fewer food and drug interactions, and lower bleeding risks. However, observational data regarding the use of DOACs, and rivaroxaban in particular, for patients with APS have yielded conflicting results.

Two previous randomized trials have evaluated use of rivaroxaban for patients with APS. The RAPS trial suggested that rivaroxaban might be effective in patients with previous venous thromboembolism (VTE) who had been taking warfarin, but follow-up was short and the trial used a surrogate measure of efficacy. The TRAPS trial, in contrast, demonstrated a higher risk of thrombotic events with rivaroxaban versus warfarin in patients with triple-positive antiphospholipid antibodies; it was limited by its early termination.

This new study conducted at six university hospitals in Spain, was a randomized, open-label, noninferiority trial with an average follow-up of nearly 3 years. It included 190 adults (64% women) with thrombotic APS. Participants had to have “objectively confirmed arterial or venous thrombosis and a positive result on antiphospholipid antibody testing on two occasions at least 3 months apart,” the researchers note.

Patients were randomized to rivaroxaban 20 mg (or 15 mg for those with reduced renal function) once daily or to dose-adjusted VKA therapy with a target international normalized ratio of 2.0 to 3.0 (or 3.1 to 4.0 in patients with a history of recurrent thrombosis). The average time in therapeutic range in the VKA group was 56%.

The primary efficacy outcome was new thrombotic events, and in the per protocol analysis, these occurred more commonly in the rivaroxaban group—11 versus six patients. Strokes accounted for all but two of the events in the rivaroxaban group; there were no strokes in the VKA arm.

Major bleeding, the primary safety outcome, occurred at similar rates in the two groups (6.3% with rivaroxaban and 7.4% with VKA). There were also no differences in any bleeding, clinically relevant nonmajor bleeding, or minor bleeding, although menorrhagia was more common in the rivaroxaban arm (22.1% vs 10.5%).

There were few deaths (five in the rivaroxaban arm and three in the VKA), with most related to cancer.

End of the Line for DOACs in APS?

Though Cortés-Hernández called the results “quite conclusive” and said they likely apply to other DOACs as well, she said there is still some uncertainty about whether there are certain subgroups of patients with APS who might benefit from a DOAC over a VKA.

And in practice, she pointed out, DOACs are still being used in select patients with APS in an off-label fashion. Of note, during the trial, not all patients who had a thrombotic event while taking rivaroxaban stopped treatment. Rivaroxaban was withdrawn in five patients, but the rest continued taking the drug with aspirin added.

This approach—adding low-dose aspirin—has not been studied in a randomized trial, but Cortés-Hernández said some patients do not want to switch to warfarin, so the antiplatelet is added to try to protect against future events while maintaining the ease of use of a DOAC.

Patient selection is key here, she indicated, pointing out that patients with previous arterial events, livedo racemosa, and valvular heart disease are at higher risk for thrombotic events while taking rivaroxaban; these patients are generally switched back to conventional warfarin therapy. In lower-risk patients who do not want to go back to a VKA, adding aspirin to the DOAC is an option, she said.

Cortés-Hernández acknowledged, however, that further studies are needed.

Clinicians need to be cautious when considering rivaroxaban use in patients with APS. Mary Cushman

Commenting for TCTMD, Mary Cushman, MD (University of Vermont Medical Center, Burlington), said via email that in the United States, long-term anticoagulation with warfarin is typically used for patients with thrombotic APS.

“In our practice, in those with one venous thrombosis who are treated initially for an acute event with a DOAC, if we then diagnose APS and they have done well on this [prescription], we usually keep them on their DOAC at full anticoagulant intensity rather than dose-reducing it (as would be done after an initial 3- to 6-month course of anticoagulation for VTE patients without APS),” Cushman said. “If they have triple-positive APS, we have a careful discussion and have been advising a switch to warfarin.”

There’s no way of knowing whether the results of this trial would apply to other DOACs, but the implication of these findings is that “clinicians need to be cautious when considering rivaroxaban use in patients with APS,” she said. Cushman noted that the study participants did not all have triple-positive antiphospholipid antibodies, as in the TRAPS trial, and that “might make clinicians even more wary of using this agent in patients even if they are single-positive or double-positive. This is why we need larger trials with well-defined, homogeneous entry criteria.”

In an accompanying editorial, Denis Wahl, MD, PhD, and Virginie Dufrost, MD (both from CHRU de Nancy, France), point out that “guidelines proposed under the auspices of the European League Against Rheumatism recommend against the use of rivaroxaban in patients with APS and triple positivity” based on the results of the TRAPS trial.

“The results of this new randomized trial support these guidelines, particularly in patients with previous arterial thromboses,” they say. “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. Thus, the data now available, including those from Ordi-Ros and colleagues, suggest that DOACs should not be prescribed for patients with high-risk APS.”

Future studies, Wahl and Dufrost add, are required to see whether there are subsets of patients with APS who might benefit from DOACs.