March-April 2018, Volume 15, Issue 2
Antiphospholipid Syndrome: Can the Direct Oral Anticoagulants Be Used?
Published on: February 21, 2018
Study Title: Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS)
ClinicalTrials.gov Identifier: 02157272
Participating Centers: Multicenter study under the leadership of University of Padova, Italy
Accrual Goal: 537 patients originally; however, the study terminated January 30, 2018, after 121 patients enrolled, because of “unbalance in the composite endpoint between arms.”
Study Design: 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.
Rationale: 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.
Comment: 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.
APS Studies Investigating the Benefit of DOACs
|Title||Clinicaltrials.gov ID||Principal Investigator (Country)||Patient Population||Treatment||Design||Outcome||Originally Expected Enrollment||Current Enrollment (as of 1/19/2018)||Funding Source(s)||Reference(s)|
|TRAPS||02157272||V. Pengo (Italy)||H/o thrombosis (arterial or venous or microvascular) + triple APLA positive||Rivaroxaban 20 mg (or 15 mg for GFR 30-50 mL/min) qd versus warfarin, INR 2-3||Randomized, open-label||Recurrent thrombosis (arterial or venous)||537||121 Enrollment terminated January 30, 2018||University of Padova, Italy||1 (No results)|
|ASTRO-APS||02295475||S.C. Woller (USA)||Patients with APS (definite, likely, or historical) and VTE ≥ 6 months ago, on anticoagulation||Apixaban 5 mg bid versus Warfarin, INR 2-3||Randomized, open-label||Pilot + feasibility study to identify, recruit, randomize + follow patients. Secondary outcomes: recurrent thrombosis, bleeding||200||41 Actively enrolling||Intermountain Health Care, Inc, USA; Bristol-Myers-Squibb||10,11 (No results)|
|None||02926170||J. Cortes (Spain)||H/o arterial or venous thrombosis + treated with acenocumarol for ≥ 6 months||Rivaroxaban vs. acenocumarol||Randomized, open-label||Recurrent thrombosis (arterial or venous)||190||190 Enrollment and 3-year follow-up completed||Hospital Universitari Vall d’Hebron Research Institute, Spain||No results|
|RAPS*||02116036||K.J. Legault, MA Crowther (Canada)||H/O venous thrombosis, currently on anticoagulation||Rivaroxaban 20 mg qd||Single-arm pilot feasibility study||Pilot + feasibility study to consent, enroll + follow patients;secondary outcomes: recurrent thrombosis, bleeding||150||81 Enrollment completed#||Multiple||No results|
Abbreviations: APLA, antiphospholipid antibody; APS, antiphospholipid syndrome; GFR, glomerular filtration rate; H/O, history of.
* Not to be confused with another APS study also called “RAPS” [Cohen H et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomized, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Hematol. 2016;3:e426-36]; this study had laboratory parameters (endogenous thrombin potential) as the primary outcome.
# Stopped early because of funding reasons.
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.
Pengo V, Banzato A, Bison E, et al. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial. Lupus. 2016;25:301-306.
Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.
Resseguier AS, Pereira B, Rieu V, et al. Direct oral anticoagulants: an alternative treatment for thrombotic antiphospholipid syndrome?. Lupus. 2017;26:1297-1303.
Kunk PR, Brown J, McShane M, et al. Direct oral anticoagulants in hypercoagulable states. J Thromb Thrombolysis. 2017;43:79-85.
Noel N, Dutasta F, Costedoat-Chalumeau N, et al. Safety and efficacy of oral direct inhibitors of thrombin and factor Xa in antiphospholipid syndrome. Autoimmun Rev. 2015;14:680-685.
Malec K, Góralczyk T, Undas A. The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome. Thromb Res. 2017;152:93-97.
Dufrost V, Risse J, Zuily S, et al. Direct oral anticoagulants use in antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? A systematic review of the literature. Curr Rheumatol Rep. 2016;19:52.
Yazici A, Unlu O, Erkan D. Comment on: "The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome". Thromb Res. 2017;157:82-83.
Dufrost V, Risse J, Kirchner S, et al. Failure of rivaroxaban to prevent thrombosis in four patients with anti-phospholipid syndrome. Rheumatology (Oxford). 2017;56:1433-1434.
Woller SC, Stevens SM, Kaplan DA, et al. Apixaban for the secondary prevention of thrombosis among patients with antiphospholipid syndrome: Study rationale and design (ASTRO-APS). Clin Appl Thromb Hemost. 2016;22:239-247.
Woller SC, Stevens SM, Kaplan DA, et al. Protocol modification of apixaban for the secondary prevention of thrombosis among patients with antiphospholipid syndrome study. Clin Appl Thromb Hemost. 2018;24:192.
Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133-1138.
Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3:848-853.
Schofield JR, Hassell K. Dosing considerations in the use of the direct oral anticoagulants in the antiphospholipid syndrome. J Clin Pharm Ther. 2018;43:104-106.
Conflict of Interests
Dr. Moll indicated no relevant conflicts of interest.
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