Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients With Antiphospholipid Syndromes

Quick Takes

  • Direct oral anticoagulant use has been associated with higher arterial thrombotic events but similar rates of venous thromboembolic events and major bleeding relative to vitamin K antagonist (VKA) use.
  • The findings of a 2022 meta-analysis suggest potential benefits for VKA use in all types of antiphospholipid syndrome (single-positive, double-positive, and triple-positive antibodies).

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous and arterial thrombotic events. Relatively small randomized controlled trials (RCTs) that compared direct oral anticoagulants (DOACs) with vitamin K antagonists (VKAs) have raised concern about excess thrombotic events with DOAC use.1-4 Khairani et al. conducted a meta-analysis of four open-label RCTs encompassing 472 patients that compared DOACs with VKAs.5

The two main efficacy outcomes of the meta-analysis were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Across the four RCTS included in the meta-analysis, the mean age was 48 years, 68% of patients were women, and 56.5% of patients had triple-positive APS. The mean follow-up time was 19 months.

Overall, the use of DOACs compared with VKAs was associated with increased odds of the composite of arterial thrombotic events (10.3% vs. 1.3%; odds ratio [OR], 5.43; 95% confidence interval [CI], 1.87-15.75; p < 0.001). The arterial thrombotic results were mainly driven by acute strokes, as there was no difference noted in acute myocardial infarction rates across the DOAC and VKA cohorts. The odds of VTE risk and major bleeding were similar between patients assigned to DOACs (1.7% vs. 1.3%; OR, 1.2; 95% CI, 0.31-4.55; p = 0.79) versus VKAs (4.3% vs. 4%; OR, 1.02; 95% CI, 0.42-2.47; p = 0.97). Pooled results indicate that patients assigned to DOACs, compared with those assigned to VKAs, had higher odds of developing arterial thrombotic events without clear effect modification on the basis of APS type (triple-positive APS vs. single-positive or double-positive APS), sex, or history of arterial thrombosis (vs. no previous arterial thrombosis).

The findings of this meta-analysis suggest that the use of DOACs is associated with higher rates of arterial thrombotic events (especially acute ischemic stroke), similar rates of VTE, and similar rates of major bleeding relative to the use of VKAs. These findings seem to be consistent regardless of patients' numbers of positive APS antibodies.


  1. 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;6:1661-70.
  2. Cohen H, Hunt BJ, Efthymiou M, et al.; RAPS Trial Investigators. 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:e426-36.
  3. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018;132:1365-71.
  4. 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;171:685-94.
  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;81:16-30.

Clinical Topics: Anticoagulation Management, Vascular Medicine

Keywords: Anticoagulants, Anticoagulation Management, Antiphospholipid Syndrome, Venous Thrombosis

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