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Rivaroxaban shows ‘no benefit, excess risk’ for antiphospholipid syndrome

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August 3, 2018

Rivaroxaban increased risk for cardiac events compared with warfarin among patients with high-risk antiphospholipid syndrome, according to results of a randomized, open-label, multicenter, noninferiority study published in Blood.

The analysis included patients with antiphospholipid syndrome who were high risk and triple positive for lupus anticoagulant, anticardiolipin and anti-2-glycoprotein I antibodies.

Patients with antiphospholipid syndrome who are triple positive are at the higher risk for a first thrombotic event, as well as at risk for a higher rate of recurrence despite antithrombotic treatment.

“Triple-positive individuals are less than 50% of those positive in one or two tests exploring the presence of antiphospholipid antibodies,” Vittorio Pengo, MD, associate professor of cardiology at University of Padova in Italy, and colleagues wrote. “Secondary prevention of thromboembolic events is the primary therapeutic goal in these patients and the mainstay treatment is warfarin, as it significantly reduces thromboembolic recurrences. However, the management of warfarin therapy is challenging, and thromboembolic events are frequent when the intensity of anticoagulation is not adequate.”

Researchers randomly assigned patients to rivaroxaban (n = 59; Xarelto, Janssen) or warfarin (n = 61) for the prevention of thromboembolic events, major bleeding and vascular death.

The trial was terminated prematurely after the enrollment of 120 patients because of an excess of events among patients assigned rivaroxaban.

Mean follow-up was 569 days.

Eleven patients (19%) in the rivaroxaban arm experienced events compared with two patients (3%) in the warfarin arm (HR = 6.7; 95% CI, 1.5-30.5).

Thromboembolic events occurred among seven patients (12%) randomly assigned rivaroxaban, including four patients with ischemic stroke and three patients with myocardial infarction. No thromboembolic events occurred among patients assigned warfarin.

“The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events as compared with warfarin, thus showing no benefit and excess risk,” the researchers wrote.

Major bleeding occurred among four patients (7%) in the rivaroxaban arm compared with two patients (3%) in the warfarin group (HR = 2.5; 95% CI, 0.5-13.6).

Researchers observed no deaths in the study population.

“The results of our trial should raise the awareness among health care personnel on the lack of efficacy of rivaroxaban in high-risk triple-positive antiphospholipid syndrome patients and may be relevant for the other trials testing direct anticoagulants in this setting,” the researcher wrote. “Results from this study cannot be translated to antiphospholipid syndrome patients without a ‘full positive’ laboratory profile. At present, the 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.” – by Cassie Homer


Disclosures: The researchers report no relevant financial disclosures.

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For patients with venous thromboembolism, direct oral anticoagulants (DOACs) — targeting either factor Xa or thrombin —  have been shown to be as effective as warfarin for initial treatment and for the prevention of recurrences. The DOACs gained regulatory agency approval without regard to the risk factors predisposing patients to VTE. There however are “special populations” who are at higher recurrence risk; one such group is patients with antiphospholipid antibody syndrome (APS), where warfarin has been the mainstay of therapy for the prevention of recurrent venous as well as arterial thrombosis to which such patients are predisposed.

Shortly after the introduction of DOACs, there were anecdotal reports of recurrences in APS patients who had been transitioned to them from warfarin.

Given the uncertainty regarding the efficacy of DOACs in APS, researchers of TRAPS compared rivaroxaban with warfarin among high-risk APS patients in an open-label, multicenter, noninferiority study. The trial stopped early after an excessive number of events occurred among patients receiving rivaroxaban 20 mg daily (n = 11 of 59, including seven with recurrent thrombosis and one cardiovascular death) compared with the vitamin K antagonist warfarin with a target INR of 2 to 3 (n = 2 of 61, both bleeds); there were four major bleeds on rivaroxaban.

APS is a heterogeneous autoimmune disorder defined by thrombosis in any vascular bed in association with persistent positivity of a lupus anticoagulant and/or levels of cardiolipin or beta2-glycoprotein I IgG/IgM greater than 40. The presence of positive results in all three laboratory tests — so called “triple positivity” — is felt to constitute a particularly high-risk population of APS patients; this laboratory profile was required for participants entering TRAPS. The population was also very high risk from a clinical perspective, as the inclusion criteria allowed entry of patients with a history of arterial thrombotic events (rivaroxaban, n = 11; warfarin, n = 14) for which there is uncertainty regarding the efficacy of DOACs. It should be noted that three patients with a history of venous thrombosis developed arterial thrombotic events in the rivaroxaban arm. In addition, 41% of patients in each arm of TRAPS had an autoimmune disease and many were receiving immunosuppressive medications. Cardiovascular risk factors, such as hypertension and hyperlipidemia, were also frequently present.

Although TRAPS was a relatively small study, its message is clear for some patients with APS; warfarin is the anticoagulant of choice for triple-positive patients. Although not addressed by this trial, any patient with arterial thrombosis in association with APS, even in the absence of “triple positivity,” should receive warfarin.

Given the heterogeneity of APS, stratifying patients with regard to recurrence risk is not straight-forward, and additional research and/or the use of new laboratory tools is required. Future trials will inform us whether lower risk APS patients with VTE can be treated with DOACs as effectively as warfarin. Until such data become available, warfarin should be the preferred anticoagulant for APS, although DOACs can be considered in lower risk patients on an individualized basis.

Kenneth A. Bauer, MD        

HemOnc Today Editorial Board Member
Beth Israel Deaconess Medical Center
Harvard Medical School

Disclosure: Bauer reports a consultant role with Janssen.