Thromboprophylaxis for Children Post-Fontan Procedure: Insights From the UNIVERSE Study

Abstract

Background Patients with single-ventricle physiology who undergo the Fontan procedure are at risk for thrombotic events associated with significant morbidity and mortality. The UNIVERSE Study evaluated the efficacy and safety of a novel liquid rivaroxaban formulation, using a body weight-adjusted dosing regimen, versus acetylsalicylic acid (ASA) in children post-Fontan. Methods and Results The UNIVERSE Study was a randomized, multicenter, 2-part, open-label study of rivaroxaban, in children who had undergone a Fontan procedure, to evaluate its dosing regimen, safety, and efficacy. Part A was the single-arm part of the study that determined the pharmacokinetics/pharmacodynamics and safety of rivaroxaban in 12 participants before proceeding to part B, whereby 100 participants were randomized 2:1 to open-label rivaroxaban versus ASA. The study period was 12 months. A total of 112 participants were enrolled across 35 sites in 10 countries. In part B, for safety outcomes, major bleeding occurred in one participant on rivaroxaban (epistaxis that required transfusion). Clinically relevant nonmajor bleeding occurred in 6% of participants on rivaroxaban versus 9% on ASA. Trivial bleeding occurred in 33% of participants on rivaroxaban versus 35% on ASA. For efficacy outcomes, 1 participant on rivaroxaban in part B had a pulmonary embolism (2% overall event rate); and for ASA, 1 participant had ischemic stroke and 2 had venous thrombosis (9% overall event rate). Conclusions In this study, participants who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group. Registration URL: https://www.clinicaltrials.gov. Identifier: NCT02846532.

Keywords: Fontan; children; major bleeding; rivaroxaban; thrombotic events.

Conflict of interest statement

Dr McCrindle has served on the scientific advisory board for Janssen R&D, LLC, Chiesi, and Esperion; was the Data and Safety Monitoring Board Chair for Amryt Pharma; and was an investigator for Janssen R&D, LLC. Dr Michelson has served on the scientific advisory board for Janssen R&D, LLC, AstraZeneca, Chiesi, and Stasys. Dr Justino has served on the scientific advisory board for Janssen R&D, LLC, and Pediastent; has been a consultant for Abiomed, Edwards Lifesciences, and Medtronic; has intellectual property for PolyVascular; and has a grant from W.L. Gore. Dr Harris received consultant/honoraria fees from Janssen R&D, LLC. Dr Pina is an employee with equity ownership of Janssen R&D, LLC. C. Peluso is an employee with equity ownership of Janssen R&D, LLC. K. Nessel is an employee with equity ownership of Janssen R&D, LLC. W. Lu is an employee with equity ownership of Janssen R&D, LLC. Dr Li has served on the scientific advisory board for Janssen R&D, LLC. The remaining authors have no disclosures to report.

Figures

Figure 1. Trial design.

ASA indicates acetylsalicylic acid; BID, twice daily; DRC, Data Review Committee; EOT, end of treatment; IDMC, independent data monitoring committee; PD, pharmacodynamics; PK, pharmacokinetics; and R, randomization.

Figure 2. UNIVERSE Study flow.

*Reasons for screen failures: of the 17 subjects, 8 did not meet inclusion criteria (2 did not have the Fontan within 4 months of enrollment, 4 did not tolerate oral feedings, and 2 had nonsatisfactory screening echocardiogram) and 11 met at least 1 exclusion criterion (3 had evidence of thrombosis on screening echocardiogram, 4 were on prohibited medications, 1 had a known contraindication to acetylsalicylic acid (ASA), and 3 were not considered appropriate candidates for the study by their physicians). DRC indicates Data Review Committee.