Rivaroxaban Misfires in Antiphospholipid Syndrome

Roxanne Nelson RN, BSN

October 17, 2019

Thrombosis is one of the clinical hallmarks of antiphospholipid syndrome (APS), but anticoagulant treatment with rivaroxaban (Xarelto, Janssen Pharmaceuticals) may not be the optimal choice.

Findings from a new randomized study failed to show that rivaroxaban was noninferior to dose-adjusted warfarin in patients with APS. In fact, patients treated with rivaroxaban had a nonstatistically significant near doubling of the risk for recurrent thrombosis.

At 3 years, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and six (6.3%) in the warfarin group. Even though the proportion of patients with major bleeding events was similar in both groups, stroke was more common in patients treated with rivaroxaban.

Senior author Josefina Cortés-Hernández, MD, PhD, Vall d'Hebrón University Hospital, Barcelona, Spain, explained that she doesn't think there is sufficient information to address all questions concerning the failure of the direct oral anticoagulants (DOACs) in APS.

"In literature there are also cases of thrombotic recurrence in APS with apixaban and dabigatran," she said. "I don't think the higher risk of arterial recurrence is only related to rivaroxaban, and the main problem is that we don't have a clear explanation for the failure at the arterial level in those patients."

The results were published October 15 in the Annals of Internal Medicine.

Long-term anticoagulation with vitamin K antagonists (VKAs) remains the standard treatment for secondary prevention of thrombosis in APS. However, recurrent thrombosis affects from 2% to 5% of patients treated with warfarin, with half of those cases occurring when the international normalized ratio (INR) is below the predetermined target range. Thus, note the authors, maintaining optimized anticoagulation to prevent recurrent thrombosis and bleeding continues to be a therapeutic challenge in this population.

A previous study suggested that rivaroxaban, a fixed-dose direct factor Xa inhibitor that does not require laboratory monitoring, may be efficacious in patients with previous venous thromboembolism. However, a second study was stopped early because of an increased risk for thrombosis in patients with triple-positive APS, although the authors urge caution in interpreting these results because of limitations that include the use of a laboratory surrogate marker as a primary end point.

Recurrent Thrombosis Higher

In the current trial, Cortés-Hernández and colleagues randomly assigned 190 adults with thrombotic APS to rivaroxaban (20 mg/d or 15 mg/d, based on renal function) or dose-adjusted VKAs (target INR, 2.0 - 3.0 or 3.1 - 4.0). The primary efficacy outcome was the proportion of patients with new thrombotic events, and the primary safety outcome was major bleeding.

Recurrent thrombosis was higher in the rivaroxaban group (risk ratio [RR], 1.83; 95% CI, 0.71 - 4.76; P for noninferiority = .29; P for VKA superiority = .20). These results "clearly exceed the defined noninferiority margin of 1.40," the authors point out.

In the intent-to-treat analysis, primary events occurred in 12 patients (12.6%) in the rivaroxaban group and six (6.3%) in the VKA group (RR, 2.0; 95% CI, 0.78 - 5.11; P for noninferiority = .57; P for VKA superiority = .13).

In the as-treated safety population, major bleeding was similar in the rivaroxaban and VKA groups (6 vs 7 patients; corrected RR, 0.86; 95% CI, 0.30 - 2.46). Overall bleeding was reported in 31 patients (32.6%) in the rivaroxaban group and 26 (27.4%) in the VKA group (RR, 1.19; 95% CI, 0.77 - 1.85). No fatal bleeding episodes were reported in either group.

When looking at secondary outcomes, the authors found that recurrent thrombotic events in patients receiving rivaroxaban were predominantly arterial, with a high rate of stroke. There were nine events versus none in the VKA group (RR, 19.00; 95% CI, 1.12 - 321.9), with a hazard ratio for time to the primary event of 1.94 (95% CI, 0.72 - 5.24; P = .19).

One patient in the rivaroxaban group developed catastrophic APS. Among patients who experienced a thrombotic event, rivaroxaban was stopped in five patients and aspirin was added for the rest. For patients in the VKA group, INR values remained within therapeutic range a mean of 56% of the time.

Cortés-Hernández explained that at the current time, it is unclear if DOACs should not be prescribed to all APS patients. "Or in some cases, assessed individually, especially among those with a lower-risk profile," she said. "However, in those cases, at the moment, I would add low-dose aspirin to prevent possible future arterial events."

Use in APS Not Recommended

In an accompanying editorial, Denis Wahl, MD, PhD, and Virginie Dufrost, MD, both from the University of Lorraine, Nancy, France, note that studies looking at other DOAC treatment strategies in this population have not supported their use. Proposed guidelines by the European League Against Rheumatism recommend against using rivaroxaban in patients with APS and triple positivity, and the "results of this new randomized trial support these guidelines, particularly in patients with previous arterial thromboses."

Data currently available suggest that DOACs should not be prescribed for patients with high-risk APS. But they also point out that "future research is needed to determine whether there is a lower-risk subset of patients with APS who might be eligible for DOAC therapy."

Steven R. Levine, MD, SUNY Distinguished Professor of Neurology and Emergency Medicine and executive vice-chair of neurology at SUNY Downstate Health Sciences University, New York City, agrees that these agents should not be used in this population, given the current data, and noted that "it's not as straightforward as we thought it was."

"It's not just thinning the blood or not having to monitor the INR; there's another mechanism at play that we have to figure out," he told theheart.org | Medscape Cardiology. "What we're finding out in many blood clot issues, such as DVTs and PEs and preventing stroke and Afib, is that this class of drug is as good as, if not better, than Coumadin."

But it doesn't seem to be the case for APS. "For this particular disease, we have two studies showing that they make it worse," Levine said. "So there is something unique about this syndrome and we shouldn't be using them until we understand this better."

The study was funded by Bayer Hispania. Cortes-Hernandez reports institutional support from Bayer Hispania to conduct the study. Several coauthors also report relationships with industry, as noted in the paper. The editorialists and Levine have no disclosures.

Ann Intern Med. Published online October 15, 2019. Abstract, Editorial

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