Rivaroxaban Versus Acetylsalicylic Acid in Children After Fontan: The UNIVERSE Study Randomized Clinical Trial

Single ventricle palliation consists of 3-stage congenital heart surgeries that ultimately culminates in the Fontan palliation performed in the first few years of life. Venous and arterial thrombotic events after Fontan procedure remain an important complication with the highest risk within the first 6 months to 2.5 years after the Fontan procedure.1 Based on population-based studies, the estimated prevalence of thromboembolic events occur in 17% to 35%, with a reported mortality of 25% due to thromboembolic complications.2,3 Meta-analyses evaluating whether thromboprophylaxis with either antiplatelet or anticoagulant therapy verses no thromboprophylaxis demonstrated a significantly lower risk of thromboembolic complications (odds ratio 0.94, 95% CI 0.19-0.92, P<0.01, I2=37%) although there was no significant difference when comparing acetylsalicylic acid (ASA) compared to warfarin (odds ratio 0.94, 95% CI 0.61-1.44, p=0.54, I2=0).4 A multicenter prospective randomized control study of antithrombotic prophylaxis in Fontan recipients published in 2011 demonstrated no significant difference in thromboembolic complications among those receiving ASA compared to warfarin (p=0.45), with high rates of thromboembolic events within the first 2 years after Fontan surgery occurring in 21% of those treated with ASA and 24% of those treated with warfarin.5 There were also challenges with maintaining therapeutic warfarin levels in these young children and there was evidence of bleeding complications in both groups.

Based on the unacceptable rates of thromboembolic complications among young patients who received the Fontan procedure, the UNIVERSE study, a prospective, open-label, phase III multicenter study in children 2 to 8 years of age with single ventricle disease and Fontan procedure within 4 months prior, were enrolled in a 2-part study evaluating dosing regimen, safety, and efficacy of liquid rivaroxaban versus ASA.6 Dosing of rivaroxaban, a direct factor Xa inhibitor, was evaluated using a model-informed drug development approach with pharmacokinetics (PK) assessed using a weight-based dosing regimen compared to adult dosing of 10 mg once daily, while the safety and efficacy was assessed compared to ASA for a 12-month period.7 This novel study design that utilizes a physiologically based PK modeling and simulation strategy followed by safety and efficacy evaluation obviated the need for dose-finding studies in an expeditious manner.

A total of 112 children were enrolled across 35 sites in 10 countries. Children who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, compared to the ASA group, although this did not reach statistical significance (overall event rate: 3% rivaroxaban vs. 9% ASA). Bleeding occurred in similar rates in both groups (33% rivaroxaban vs. 35% of ASA), although major bleeding (epistaxis requiring transfusion) only occurred in one subject who was receiving rivaroxaban. Based on these findings, rivaroxaban appears to be a novel oral anticoagulant with liquid formation for young children with Fontan circulation that is safe, efficacious, and does not require regular laboratory monitoring.


  1. McCrindle BW, Manlhiot C, Cochrane A, et al. Factors associated with thrombotic complications after the Fontan procedure: a secondary analysis of a multicenter, randomized trial of primary thromboprophylaxis for 2 years after the Fontan procedure. J Am Coll Cardiol 2013;61:346-53.
  2. Balling G, Vogt M, Kaemmerer H, Eicken A, Meisner H, Hess J. Intracardiac thrombus formation after the Fontan operation. J Thorac Cardiovasc Surg 2000;119:745-52.
  3. Yousef N, Philips M, Shetty I, Cui VW, Zimmerman F, Roberson DA. Transesophageal echocardiography of intracardiac thrombus in congenital heart disease and atrial flutter: the importance of thorough examination of the Fontan. Pediatr Cardiol 2014;35:1099-107.
  4. Alsaied T, Alsidawi S, Allen CC, Faircloth J, Palumbo JS, Veldtman GR. Strategies for thromboprophylaxis in Fontan circulation: a meta-analysis. Heart 2015;101:1731-37.
  5. Monagle P, Cochrane A, Roberts R, et al. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children. J Am Coll Cardiol 2011;58:645-51.
  6. McCrindle BW, Michelson AD, Van Bergen AH, et al. Thromboprophylaxis for children post-Fontan procedure: insights from the UNIVERSE study. J Am Heart Assoc 2021;10:e021765.
  7. Zhu P, Willmann S, Zhou W, et al. Dosing regimen prediction and confirmation with rivaroxaban for thromboprophylaxis in children after the Fontan procedure: insights from the Phase III UNIVERSE study. J Clin Pharmacol 2022;62:220-31.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Cardiac Surgery and CHD and Pediatrics, Congenital Heart Disease, CHD and Pediatrics and Interventions, CHD and Pediatrics and Quality Improvement, Interventions and Vascular Medicine, Heart Failure and Cardiomyopathies

Keywords: Fontan Procedure, Warfarin, Rivaroxaban, Factor Xa Inhibitors, Anticoagulants, Fibrinolytic Agents, Prospective Studies, Epistaxis, Laboratories, Odds Ratio, Prevalence, Venous Thromboembolism, Aspirin, Drug Development, Child

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