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Original research
Direct oral anticoagulants versus vitamin K antagonists in patients with antiphospholipid syndrome: systematic review and meta-analysis
  1. Nazariy Koval1,
  2. Mariana Alves2,3,4,
  3. Rui Plácido5,6,
  4. Ana G Almeida5,6,
  5. João Eurico Fonseca4,7,
  6. Joaquim J Ferreira2,4,8,
  7. Fausto J Pinto5,6 and
  8. Daniel Caldeira2,5,6
  1. 1Universidade de Lisboa Faculdade de Medicina, Lisbon, Portugal
  2. 2Laboratório de Farmacologia Clinica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
  3. 3Medicina III, Hospital Pulido Valente (CHULN), Lisboa, Portugal
  4. 4Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
  5. 5Centro Cardiovascular da Universidade de Lisboa (CCUL), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
  6. 6Cardiology Department, Hospital Universitário de Santa Maria (CHULN), Lisboa, Portugal
  7. 7Serviço de Reumatologia, Centro Hospitalar Universitario Lisboa Norte (CHULN), Lisboa, Portugal
  8. 8CNS - Campus Neurológico Sénior, Torres Vedras, Portugal
  1. Correspondence to Dr Daniel Caldeira; dgcaldeira{at}


Background Despite vitamin K antagonists (VKA) being the gold standard in the prevention of thromboembolic events in antiphospholipid syndrome (APS), non-vitamin K antagonists oral anticoagulants/direct oral anticoagulants (DOACs) have been used off-label.

Objective We aimed to perform a systematic review comparing DOACs to VKA regarding prevention of thromboembolic events, occurrence of bleeding events and mortality in patients with APS.

Methods An electronic database search was performed through MEDLINE, CENTRAL and Web of Science. After data extraction, we pooled the results using risk ratio (RR) and 95% CI. Heterogeneity was assessed using the I². The outcomes considered were all thromboembolic events as primary, and major bleeding, all bleeding events and mortality as secondary. Evidence confidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology.

Results We included 7 studies and a total of 835 patients for analyses. Thromboembolic events were significantly increased in DOACs arm, compared with VKA—RR 1.69, 95% CI 1.09 to 2.62, I²—24%, n=719, 6 studies. In studies using exclusively rivaroxaban, which was the most representative drug in all included studies, the thromboembolic risk was increased threefold (RR 3.36, 95% CI 1.53 to 7.37). The risks of major bleeding, all bleeding events and mortality were not significantly different from control arm. The grade of certainty of our results is very low.

Conclusions Current evidence suggests DOACs use, particularly rivaroxaban, among patients with APS, is less effective than VKA since it is associated with 69% increased risk of thromboembolic events.

Trial registration number CRD42020216178.

  • antiphospholipid syndrome
  • autoantibodies
  • autoimmune diseases

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Contributors NK and DC contributed to the concept and design of this review. NK, MA and DC contributed to data acquisition and data analysis. NK, MA, RP, AGA, JEF, JFF, FJP and DC contributed to interpretation of data, critically revised the manuscript and gave final approval of the submitted manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.