Antiphospholipid Syndrome: Can the Direct Oral Anticoagulants Be Used?

Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS)

02157272

Multicenter study under the leadership of University of Padova, Italy

537 patients originally; however, the study terminated January 30, 2018, after 121 patients enrolled, because of “unbalance in the composite endpoint between arms.”

TRAPS is a randomized, controlled, open-label, noninferiority study investigating rivaroxaban 20 mg once daily compared to warfarin (target international normalized ratio of 2.0-3.0) in patients with definite antiphospholipid syndrome (APS) with a history of thrombosis, either arterial, venous or biopsy-proven microvascular, and triple-positive antiphospholipid antibody (APLA) tests.¹  “Positivity” is defined by at least moderately elevated anticardiolipin and anti–β₂-glycoprotein-I IgG or IgM antibodies as classified by the Sydney criteria,²  and a positive lupus anticoagulant. The primary outcome is a composite of acute thrombosis (arterial or venous), major bleeding, and death.

Warfarin is the main anticoagulant used in patients with APS who require anticoagulation, but management with warfarin can be challenging. Use of a direct oral anticoagulant (DOAC) with a predictable anticoagulant effect and not requiring monitoring would be an attractive treatment alternative. Some retrospective cohort publications have suggested that DOACs may be an acceptable and safe alternative to warfarin in the secondary prevention of thrombosis in APS,^3-6  but other publications have cautioned against their use because of the risk of DOAC failure.^7-9  Prospective, randomized data are obviously needed to determine efficacy and safety of DOACs in patients with APS.

The strengths of the TRAPS trial are its prospective, randomized design; relatively large size (anticipated n = 537); homogeneous patient population by laboratory parameters (all patients are triple positive for APLA); and enrollment of the higher thrombogenic APS patients (i.e., those who are triple positive). The study was prematurely terminated at the end of January 2018 when an interim analysis showed an “unbalance in the composite endpoint between arms.” The potential weaknesses included the study’s large targeted enrollment number, making sufficient patient enrollment challenging given that APS with triple APLA positivity is uncommon; however, these potential downsides are now moot, as the study has been terminated. A weakness of the study may be the fact that, by clinical criteria, an inhomogeneous patient population is enrolled (i.e., APS patients with venous as well as with arterial thrombosis), which may make conclusive subgroup analyses difficult, if not impossible, given limited subgroup sizes. In addition, as only triple APLA–positive, and, thus, fairly prothrombotic patients were enrolled, the findings of the study may not apply to less prothrombotic patients (i.e., those who are positive for only one or two of the three APLA tests recommended in the Sydney criteria. Furthermore, as only rivaroxaban is being compared to warfarin in this trial, the findings may not apply to other DOACs, particularly the twice-daily dosed treatments.

Other APS studies investigating the benefit of DOACs are currently ongoing, or publication of results pending (Table).^10,11  An interim analysis of the TRAPS study that is presently ongoing, and publication of the study by Dr. Jorge Cortes and colleagues (Table) in the near future will hopefully shed further light on the safety and efficacy of using a DOAC in patients with APS. Until data from these studies are available, I discuss with the patient who has APS and needs to be on an anticoagulant that 1) no solid data exist regarding the use of DOACs in APS, and that it is not known whether the DOACs are as effective as warfarin, less effective, or more effective; and 2) some patients with APS develop new thromboses in spite of being on warfarin,^12,13  and recurrent thrombosis can also occur on a DOAC.

If a patient with APS and I decide to start a DOAC, my general approach is to use one of the twice-daily rather than once-daily dosed DOACs, as this leads to more steady drug levels throughout a 24-hour period. The thought is that more steady levels may lead to a more effective anticoagulant effect in these very prothrombotic patients, particularly those who are triple positive. However, no data exist that this theory is correct. A recent case report publication with discussion of the pharmacokinetics/pharmacodynamics of DOACs similarly suggests a twice- rather than once-daily dosed DOAC in patients with APS.¹⁴  If a DOAC is used, I use the full dose (apixaban 5 mg twice daily, dabigatran 150 mg twice daily) rather than the reduced doses studied for venous thromboembolism in trials such as the AMPLIFY-EXTENSION trial. Whether a patient with APS and an arterial thrombosis should be treated with an antiplatelet agent, an anticoagulant drug, or a combination of both, is an altogether different question and is not being addressed by these studies. If a clinician chooses an anticoagulant drug (with or without aspirin) in a patient with APS and an arterial thrombotic event, it might at present be better (though non–evidence-based) to choose warfarin rather than a DOAC, based on limited existing data on the performance of DOACs in patients with arterial thromboses and APS.¹¹ 

For the clinician who treats patients with APS, it is exciting to hear that the TRAPS study was prematurely terminated because of an “unbalance in the composite endpoint between arms”. It suggests that we will learn something clinically impactful once the data are made publicly available.