Direct oral anticoagulants (DOACs) are the standard of care for anticoagulation following a first episode of venous thromboembolism (VTE) in the general population, however, special considerations apply to their use in patients with antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE)-associated APS.

In 2019, the European Medicines Agency (EMA) recommended against the use of DOACs in patients with APS, particularly those who are triple positive for antiphospholipid antibodies (aPL).¹ It must be emphasized that the EMA recommendation does not constitute a contraindication to the use of DOACs in APS.² The EMA recommendation was based on an analysis by the Pharmacovigilance Risk Assessment Committee (PRAC), triggered by the TRAPS (Trial on Rivaroxaban in AntiPhospholipid Syndrome) randomised controlled trial (RCT) of rivaroxaban 20 mg od versus warfarin, target international normalised ratio (INR) range 2.0–3.0, in patients with thrombotic APS and triple positive aPL.³ However, the overall clinical trial data on comparison of a DOAC versus warfarin/alternative vitamin K antagonist (VKA) in patients with APS suggest that a more nuanced approach is required.

The RAPS (Rivaroxaban versus warfarin to treat patients with thrombotic AntiphosPholipid Syndrome, with or without SLE) RCT, the first trial of a DOAC versus warfarin in patients with APS, concluded that rivaroxaban could be an effective and safe alternative in patients with APS and VTE requiring standard-intensity anticoagulation.⁴ In contrast to RAPS, subsequent DOAC RCTs included heterogenous patient populations with respect to thrombotic phenotype (venous and/or arterial thrombosis, the latter excluded in RAPS). A meta-analysis of the four DOAC RCTs in patients with APS found a significantly higher risk of arterial thrombosis during treatment with DOACs compared to warfarin/VKA, with the risk of VTE not increased.⁵

The International Society on Thrombosis and Haemostasis (ISTH) guidance recommends, for patients with APS: (1) consideration of continuation of the DOAC in single or double aPL positive non-‘high risk’ APS patients who have been on a DOAC as standard of care treatment (for the general population) following a first episode of VTE; and (2) against the use of DOACs in patients with triple aPL-positivity or arterial thrombosis.⁶

All the DOAC RCTs in APS patients used standard treatment dose DOAC,⁵ or prophylactic and standard treatment dose DOAC.^{5 7} The ongoing RISAPS (Rivaroxaban in Stroke Patients with APS) Phase IIb proof of principle RCT seeks to demonstrate non-inferior efficacy and safety of high-intensity rivaroxaban versus high-intensity warfarin in patients with APS-associated ischaemic stroke, transient ischaemic attack (TIA), or other ischemic brain injury.⁸ This trial is distinct from previous RCTs of DOAC use in APS patients in that it: (1) restricts participant inclusion to the specific thrombotic subgroup of previous ischaemic stroke, TIA or other ischaemic brain injury; and (2) employs a high intensity dose of DOAC, rivaroxaban 15 mg bd, intended to be analogous to high-intensity warfarin, target INR range 3.0–4.0, the latter being the standard of care in the RISAPS trial.

References

1. EMA/PRAC/219985/2019. Pharmacovigilance Risk Assessment Committee (PRAC). [Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-8-11-april-2019-prac-meeting_en.pdf accessed 18 June 2024.

2. Xarelto (rivaroxaban) 15 mg and 20 mg film coated tablets. Bayer ag. Summary of product characteristics. [Available from: https://www.medicines.org.uk/emc/product/2794/smpc accessed 18 June 2024.

3. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365–71. doi: 10.1182/blood-2018-04-848333.

4. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, Phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):e426–36. doi: 10.1016/s2352-3026(16)30079-5.

5. Khairani CD, Bejjani A, Piazza G, et al. Direct oral anticoagulants vs vitamin K antagonists in patients with antiphospholipid syndromes: Meta-analysis of randomized trials. J Am Coll Cardiol. 2023;81(1):16–30. doi: 10.1016/j.jacc.2022.10.008.

6. Zuily S, Cohen H, Isenberg D, et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: Guidance from the scientific and standardization committee of the international society on thrombosis and haemostasis. J Thromb Haemost. 2020;18(9):2126–37. doi: 10.1111/jth.14935.

7. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: A randomized trial. Blood Adv. 2022;6(6):1661–70. doi: 10.1182/bloodadvances.2021005808.

8. Mittal P, Gafoor R, Sayar Z, et al. Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): Protocol for a randomised controlled, Phase IIb proof-of-principle trial. Res Pract Thromb Haemost. 2024:102468. doi: https://doi.org/10.1016/j.rpth.2024.102468.

Learning Objectives At the end of this presentation participants will be able to:

• Describe the standard anticoagulation treatment for patients with thrombotic APS

• Discuss the EMA’s recommendation against the use of DOACs in patients with APS

• Describe the observations on thrombosis associated with DOAC use in patients with APS

• Discuss international guidance on DOAC use in patients with thrombotic APS