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.

New Anticoagulants in Neonates, Children, and Adolescents

“…For the evaluation of the efficacy and safety of pediatric DOACs and thus for the implementation of the PIPs 34 of the EMA mentioned at the beginning, there were three large, multinational, and thus multicenter studies: the DIVERSITY trial for dabigatran 35 and the EINSTEIN and the UNIVERSE trials for rivaroxaban. 34,36 In addition, there was also a single-arm phase III study assessing dabigatran for extended secondary venous thromboembolism (VTE) prevention. 37 In further DOACs studies they identified, Branstetter et al counted 16 neonates, 152 non-neonatal infants (>30 days to <2 years), 351 children, and 488 adolescents.…”

“…In all three trials, there were two types of endpoints: primary endpoints on the efficacy of the two DOACs compared with standard therapy and secondary endpoints related to adverse effects and the need for therapy adjustments. 35,36,39 The DIVERSITY and EINSTEIN trials were in children with acute VTE, and the UNIVERSE trial was in children post Fontan procedure.…”

“…In all three trials, there were two types of endpoints: primary endpoints on the efficacy of the two DOACs compared with standard therapy and secondary endpoints related to adverse effects and the need for therapy adjustments. 35 36 39…”

“…Therefore, the safety profile compared with the SoC was similar and, in the efficacy results, a trend toward less thrombotic events could be demonstrated in the rivaroxaban group (►Table 4). 36 The UNIVERSE study (thromboprophylaxis for children post-Fontan procedure) has been submitted for approval in the United States. As this study was not part of the PIP agreed with the EMA, it has not yet been submitted in the European Union.…”

Increased Risk for Thromboembolism After Fontan Surgery: Considerations for Thromboprophylaxis

“…The UNIVERSE study compared thromboprophylaxis with rivaroxaban or aspirin in 112 children post-Fontan surgery and revealed that patients who received rivaroxaban had a similar safety profile to those who received aspirin. A lower thrombotic event rate was also observed in the rivaroxaban group (2% vs. 9%) however this difference was statistically insignificant ( 76 ).…”