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Meta-Analysis
. 2023 Jan 3;81(1):16-30.
doi: 10.1016/j.jacc.2022.10.008. Epub 2022 Oct 31.

Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes: Meta-Analysis of Randomized Trials

Candrika D Khairani  1 , Antoine Bejjani  1 , Gregory Piazza  2 , David Jimenez  3 , Manuel Monreal  4 , Saurav Chatterjee  5 , Vittorio Pengo  6 , Scott C Woller  7 , Josefina Cortes-Hernandez  8 , Jean M Connors  9 , Yogendra Kanthi  10 , Harlan M Krumholz  11 , Saskia Middeldorp  12 , Anna Falanga  13 , Mary Cushman  14 , Samuel Z Goldhaber  2 , David A Garcia  15 , Behnood Bikdeli  16
Affiliations
Meta-Analysis

Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes: Meta-Analysis of Randomized Trials

Candrika D Khairani et al. J Am Coll Cardiol. .

Abstract

Background: The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial.

Objectives: The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: arterial thrombosis; bleeding; mortality; stroke; venous thromboembolism.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Piazza has received research support from Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation; and has received consulting fees from Bristol Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, Namsa, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. Dr Jiménez has received research support from Daiichi-Sankyo and Sanofi; and has received consulting fees from Bristol Myers Squibb/Pfizer Alliance, Daiichi-Sankyo, Leo Pharma, Rovi, and Sanofi. Dr Monreal has received research support from Sanofi, Leo, and Rovi; and has received consulting fees from Sanofi. Dr Pengo has received lecture fees from Werfen Group. Dr Cortes-Hernandez has received institutional research funding from Bayer Hispania to conduct the APS RCT. Dr Connors has received research funding to her institution from CSL Behring; has received consulting fees from Abbott; has received honoraria for lectures from Bristol Myers Squibb, Roche, and Sanofi; and has participated on the advisory board of Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the submitted work. Dr Kanthi is an inventor on a pending patent application by the University of Michigan on the use of biogases in vascular disease (US202201670756A1); and is supported by the National Heart, Lung, and Blood Institute Intramural Research Program and the Lasker Foundation. Dr Krumholz has received (within the last 3 years) expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, the Arnold and Porter Law Firm, and the Martin/Baughman Law Firm; is a cofounder of Refactor Health, an enterprise health care artificial intelligence–augmented data management company, and HugoHealth, a personal health information platform; and is associated with contracts through Yale University from Johnson and Johnson. Dr Middeldorp has received grants and personal fees from Daiichi-Sankyo; has received grants and personal fees from Bayer, Pfizer, and Boehringer Ingelheim; and has received personal fees from Portola/Alexion, Abbvie, Bristol Myers Squibb Pfizer, Norgine, and Viatris, all paid to her institution. Dr Falanga has received honoraria/consulting fees from Stago, Sanofi, Daiichi-Sankyo, Leo Pharma, and Pfizer. Dr Goldhaber has received research support from Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen, National Heart, Lung, and Blood Institute, and Pfizer; and has received consulting fees from Agile, Bayer, and Pfizer. Dr Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of IVC filters; and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital and a Career Development Award from the American Heart Association and VIVA Physicians (#938814). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Graphical summary of trial characteristics.
*Patients with a history of recurrent thrombosis were assigned to an INR of 3.1 to 4 in the VKA arm. ✝In ASTRO-APS, after 25 patients were randomized, all patients in the apixaban arm had their dose increased to 5 mg twice daily. ‡Ordi-Ros et al. used median and IQR for age. §In the ASTRO-APS trial, 31% had historical APS in the apixaban group, and 34% had historical APS in the VKA group. APS = antiphospholipid syndrome; ATE = arterial thrombotic events; BMI = body mass index; INR = international normalized ratio; IQR = interquartile range; VKA = vitamin-K antagonist; VTE = venous thromboembolism.
Figure 2.
Figure 2.. Composite of arterial thrombotic events (A), MI (B), and stroke (C).
Pooled results revealed higher odds of arterial thrombotic events in patients assigned to DOACs. The rate of stroke was higher with DOACs, while the rate of MI was not significantly different between the two groups. CI = confidence interval; DOACs = direct oral anticoagulants; MI = myocardial infarction; VKAs = vitamin-K antagonists.
Figure 3.
Figure 3.. VTE (A), DVT (B), and PE (C).
Pooled results showed no significant difference in the rate of VTE between DOACs and VKAs. The rates of DVT and PE were not significantly different among the two groups, either. CI = confidence interval; DOACs = direct oral anticoagulants; DVT = deep vein thrombosis; PE = pulmonary embolism; VKAs = vitamin-K antagonists; VTE = venous thromboembolism.
Figure 4.
Figure 4.. Major bleeding and clinically relevant non-major bleeding.
Pooled results suggest no significant difference in the rates of major bleeding (A) and CRNMB (B) between patients receiving DOACs and patients receiving VKAs. CI = confidence interval; CRNMB = clinically relevant non-major bleeding; DOACs = direct oral anticoagulants; VKAs = vitamin-K antagonists. Abbreviations as in other Figures.
Figure 5.
Figure 5.. Pre-specified subgroup analysis.
Pooled results indicate that patients assigned to DOACs compared with patients assigned to VKAs had higher odds of developing arterial thrombotic events without clear effect modification based on the type of APS (triple-positive vs any other combination), sex, or history of arterial thrombosis (vs no prior arterial thrombosis). The rates of VTE and major bleeding were not significantly different between the two treatment arms, regardless of the subgroup category.
Central Illustration.
Central Illustration.. Use of DOACs versus VKAs in thrombotic APS.
In this systematic review and meta-analysis of RCTs comparing DOACs to VKAs in patients with thrombotic APS, the results were limited by the small number of patients (472 among 4 studies) and the open-label status of the trials. Overall results indicated that in patients with thrombotic APS, DOACs were associated with significantly increased odds of subsequent arterial thrombotic events, an effect that appeared mostly driven by the increased rate of stroke, compared with VKAs. No significant differences were observed with regards to the odds of VTE or major bleeding. There was no major modification of the effect across subgroups. These results would favor the use of VKAs in patients with thrombotic APS. APS = antiphospholipid syndrome; DOACs = direct oral anticoagulants; RCTs = randomized controlled trials; VKAs = vitamin-K antagonists, VTE = venous thromboembolism.
See this image and copyright information in PMC

Comment in

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