Josep Ordi-Ros, MD, PhD; Luis Sáez-Comet, MD, PhD; Mercedes Pérez-Conesa, MD; Xavier Vidal, MD, PhD; Antoni Riera-Mestre, MD, PhD; Antoni Castro-Salomó, MD, PhD; Jordi Cuquet-Pedragosa, MD; Vera Ortiz-Santamaria, MD; Montserrat Mauri-Plana, MD, PhD; Cristina Solé, PhD; Josefina Cortés-Hernández, MD, PhD
Note: The corresponding author had full access to all data and final responsibility for the decision to submit the manuscript for publication.
Acknowledgment: The authors thank the Catalan Lupus Foundation and all the patients who participated in the trial; the investigators who recruited patients to the study; and the research staff who assisted with patient recruitment, data collection, biomarker measurements, and data management.
Financial Support: From Bayer Hispania.
Disclosures: Drs. Ordi-Ros and Cortés-Hernández report institutional support from Bayer Hispania to conduct the study. Dr. Ortiz-Santamaria reports personal fees and nonfinancial support from Pfizer, Janssen, Lilly, GSK, Novartis, Roche, and Abbott outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0291.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The following data will be made available with publication: deidentified participant data (available from Dr. Josefina Cortés-Hernández; e-mail, firstname.lastname@example.org). The following supporting documents will be made available with publication: informed consent form (available from Dr. Josefina Cortés-Hernández; e-mail, email@example.com). These data will be made available to researchers whose proposed use of the data has been approved for a specified purpose, with investigator support, and with a signed data access agreement (no restrictions).
Corresponding Author: Josefina Cortés-Hernández, MD, PhD, Department of Internal Medicine, Rheumatology Research Group, Vall d'Hebrón University Hospital Research Institute, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Ordi-Ros, Vidal, and Solé: Vall d'Hebrón University Hospital Research Institute, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain.
Drs. Sáez-Comet and Pérez-Conesa: Servicio de Medicina Interna, Hospital Universitario Miguel Servet, Paseo Isabel La Católica 9, 50009, Zaragoza, Spain.
Dr. Riera-Mestre: Internal Medicine Department, L'Hospitalet de Llobrega, Feixa llarga s/n, 08907, Barcelona, Spain.
Dr. Castro-Salomó: Internal Medicine Department, Sant Joan de Reus University Hospital, Sant Joaquim 42 1-3, 43204, Reus, Spain.
Drs. Cuquet-Pedragosa and Ortiz-Sanatmaria: Granollers University Hospital, Avinguda Francesc Ribas s/n, 08402, Granollers, Spain.
Dr. Mauri-Plana: Department of Internal Medicine, Mataro Hospital, Carrer de Cirera, 230, 08304, Mataró, Spain.
Dr. Cortés-Hernández: Department of Internal Medicine, Rheumatology Research Group, Vall d'Hebrón University Hospital Research Institute, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain.
Author Contributions: Conception and design: J. Ordi-Ros, M. Pérez-Conesa, X. Vidal, J. Cortés-Hernández.
Analysis and interpretation of the data: J. Ordi-Ros, X. Vidal, A. Castro-Salomó, C. Solé, J. Cortés-Hernández.
Drafting of the article: J. Ordi-Ros, L. Sáez-Comet, X. Vidal, A. Riera-Mestre, C. Solé, J. Cortés-Hernández.
Critical revision for important intellectual content: J. Ordi-Ros, L. Sáez-Comet, X. Vidal, A. Castro-Salomó, J. Cuquet-Pedragosa, C. Solé, J. Cortés-Hernández.
Final approval of the article: J. Ordi-Ros, L. Sáez-Comet, M. Pérez-Conesa, X. Vidal, A. Riera-Mestre, A. Castro-Salomó, J. Cuquet-Pedragosa, V. Ortiz-Santamaria, M. Mauri-Plana, C. Solé, J. Cortés-Hernández.
Provision of study materials or patients: J. Ordi-Ros, L. Sáez-Comet, M. Pérez-Conesa, A. Castro-Salomó, V. Ortiz-Santamaria, J. Cortés-Hernández.
Statistical expertise: X. Vidal.
Obtaining of funding: J. Ordi-Ros, J. Cortés-Hernández.
Administrative, technical, or logistic support: J. Ordi-Ros, L. Sáez-Comet, J. Cortés-Hernández.
Collection and assembly of data: J. Ordi-Ros, L. Sáez-Comet, M. Pérez-Conesa, X. Vidal, A. Riera-Mestre, A. Castro-Salomó, J. Cuquet-Pedragosa, M. Mauri-Plana, J. Cortés-Hernández.
The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain.
To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS.
3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36)
6 university hospitals in Spain.
190 adults (aged 18 to 75 years) with thrombotic APS.
Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis).
The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding.
After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease.
Anticoagulation intensity was not measured in the rivaroxaban group.
Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non–statistically significant near doubling of the risk for recurrent thrombosis.
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;:. [Epub ahead of print 15 October 2019]. doi: https://doi.org/10.7326/M19-0291
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Published: Ann Intern Med. 2019.
Cardiology, Hospital Medicine, Neurology, Stroke, Valvular Heart Disease.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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