Letter to the Editor: Choosing an Anticoagulant in Patients With APS Free

In the December 2023 issue of “You Make the Call,” Shruti Chaturvedi, MBBS, MS, discussed treatment options for a female patient presenting with a left cerebrovascular accident likely due to contraceptive use and positive antiphospholipid antibodies (APLAs), with a recommendation for warfarin and aspirin therapy. Following the publication of four randomized trials of direct oral anticoagulants (DOACs) versus warfarin in patients with antiphospholipid syndrome (APS), there has been greater insecurity in the medical community on how to best anticoagulate these patients. Here, two readers continue the conversation, raising questions about whether a DOAC with aspirin may be as good a choice as warfarin with aspirin in patients with APS who are positive for a single APLA.

Dr. Chaturvedi’s commentary about the management of a 27-year-old female patient with oral contraceptive (OCP)-associated stroke who is positive for a single APLA is well written and to the point. We agree with the recommended combination of an anticoagulant plus aspirin in this patient and with all comments relating to the MTHFR C677T polymorphism and homocysteine-lowering therapy.

However, we wish to highlight that it is unclear that this patient needs to be on warfarin with aspirin rather than a DOAC with aspirin because, in a patient like this, warfarin is not known to be superior to a DOAC. Our arguments that a DOAC with aspirin may be as good a choice as warfarin with aspirin are as follows:

• Selection bias in existing trials. The main argument is that the four randomized trials comparing DOACs to vitamin K antagonists (VKA)^1-4 and the subsequent meta-analysis of these trials⁵ may be affected by selection bias. Given that the patients enrolled were those with APS (i.e., they must have been positive for APLA twice, at least three months apart) and an indication for being on an anticoagulant, they most likely had been treated with a VKA before randomization. It is known that VKAs have a high failure rate in patients with APS: 20% or more of patients with APS treated with a VKA for an arterial occlusive event (like the patient under discussion) experience recurrent thrombotic events.⁶ It is unlikely that such patients would have been enrolled into the aforementioned trials in which they could have been randomized to receive a VKA, which had previously failed them. Thus, participants in these trials were probably those who were more likely to continue to do well on a VKA.
• Single-positive APS. The patient under discussion is only single-APLA positive. The above-mentioned meta-analysis did not show that a VKA was more effective than a DOAC in patients with either single- or double-APLA–positive status as opposed to those who were triple-positive.⁵
• Concurrent aspirin use. This patient will also be on aspirin. The effect of aspirin when given together with an anticoagulant was, unfortunately, not addressed in the meta-analysis.⁵ We wish a subgroup analysis had been done to determine whether DOAC failure occurred mostly in the patients who were on an anticoagulant alone.
• The role of estrogen. This patient is no longer on an OCP, and thus may be less prothrombotic than at the time of her stroke.

Keeping these four points in mind, we think a discussion with a patient like this is key, highlighting the limitations of existing data. The newly published APS diagnostic criteria^7,8 will hopefully guide future studies to facilitate a better understanding of how best to treat unique patients with APLA. Until then, one needs to recognize the limitations of existing data and cannot be dogmatic about most treatment decisions.

Stephan Moll, MD
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Jori May, MD
University of Alabama
Birmingham, Alabama

References

1. Pengo V, Hoxha A, Andreoli L, et al. Trial of rivaroxaban in antiphospholipid syndrome (TRAPS): two-year outcomes after the study closure. J Thromb Haemost. 2021;19(2):531-535.
2. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019;171(10):685-694.
3. 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):1661-1670.
4. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erthematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):e426-e436.
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.
6. Ortel TL, Meleth S, Catellier D, et al. Recurrent thrombosis in patients with antiphospholipid antibodies and an initial venous or arterial thromboembolic event: A systematic review and meta-analysis. J Thromb Haemost. 2020;18(9):2274-2286.
7. Barbhaiya M, Zuily S, Naden R, et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Ann Rheum Dis. 2023;82:1258-1270.
8. Crowther M, Erkan D. A new approach to antiphospholipid antibody syndrome. Res Pract Thromb Haemost. 2023;7(7):102226.

Response from Dr. Chaturvedi:

I appreciate the points that Drs. May and Moll make regarding navigating anticoagulant choice in patients with APS and agree that shared decision-making is critical in the absence of compelling data on anticoagulant choice for individuals with lower-risk APLA profiles and thrombosis. I remain cautious regarding DOAC use in patients with arterial events, given that the excess of recurrent thrombosis in the DOAC arms of recent trials was driven by arterial events, predominantly stroke.^1-3

However, as my colleagues point out, currently available analyses do not account for the use of aspirin.⁴ Future studies, both clinical trials and real-world observational data, are needed to better understand how to personalize antithrombotic therapy in individual patients with APLAs. I look forward to working with my colleagues in thrombosis and APS to address these issues.

Shruti Chaturvedi, MBBS, MS
Johns Hopkins University
Baltimore, Maryland

References

1. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365-1371.
2. 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):1661-1670.
3. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019;171(10):685-694.
4. 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

The content of Letters to the Editor is the opinion of the author and does not represent the official position of the American Society of Hematology unless so stated.