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Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes
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The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial.
The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs).
We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used.
Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I2 = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I2 = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I2 = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I2 = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups.
Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.
Disclosure statements are available on the authors' profiles:
Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes: Meta-Analysis of Randomized TrialsJ Am Coll Cardiol 2023 Jan 03;81(1)16-30, CD Khairani, A Bejjani, G Piazza, D Jimenez, M Monreal, S Chatterjee, V Pengo, SC Woller, J Cortes-Hernandez, JM Connors, Y Kanthi, HM Krumholz, S Middeldorp, A Falanga, M Cushman, SZ Goldhaber, DA Garcia, B Bikdeli
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Thrombotic antiphospholipid syndrome is an inflammatory condition associated with excess risk of venous and arterial thrombosis. With many ancillary benefits of direct oral anticoagulants (DOACs), some randomized clinical trials (RCTs) tested the effects of DOACs compared with standard treatment (vitamin-K antagonists [VKAs]) in patients with thrombotic antiphospholipid syndrome. Although in some of these individual trials there was concern for excess thrombotic events with DOACs, and premature termination of the trials, the number of enrollees and events in individual trials were small, leading to uncertainty about risks and benefits of DOACs in these patients.
This systematic review and meta-analysis followed a prespecified study protocol (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022268035). After a comprehensive literature search, four individual RCTs met the study eligibility criteria, three that compared rivaroxaban with VKAs and one that compared apixaban with VKAs. Overall, being assigned to DOACs compared with VKAs was associated with an excess risk in arterial thrombotic events (OR, 5.43; 95% CI, 1.87–15.75; P < .001). This risk was largely driven by a 10-fold increase in the odds of stroke (OR, 10.74; 95% CI, 2.29–50.38; P < .001), whereas the odds of subsequent venous thromboembolism (OR, 1.20; 95% CI, 0.31–4.55; P < .001) or major bleeding (OR, 1.02; 95% CI, 0.42–2.47, P = .97) did not differ significantly between the two groups. Importantly, the study prespecified assessment of the consistency of results in three key subgroups by antiphospholipid antibody status (triple-positive vs not), based on whether there was preexisting arterial thrombosis versus not, and by sex (women versus men). There was no evidence of effect modification based on triple-positive antibody status, and the increased odds of arterial thrombotic events was observed consistently (P for group difference = .80). Similarly the results were consistent whether or not there was a history of arterial thrombotic events prior to enrollment (P for group difference = .90). Although the excess risk was numerically more pronounced in women than men (OR, 10.61 vs 2.77), the test for subgroup difference was not significant (P = .20).
In sum, findings from this study raise concern about excess risk of subsequent arterial thrombotic events in patients with thrombotic antiphospholipid syndrome who are treated with DOACs, with consistent findings across clinical subgroups. Additional studies are needed to better understand in which patient subgroups testing for antiphospholipid antibodies (and confirmatory retesting at at least 12 weeks) is reasonable to identify antiphospholipid syndrome.