Adults with Fontan palliation face variable risks of thrombosis and bleeding. The optimal thromboprophylaxis strategy remains unclear. There is a balance between the risk of thromboembolism and bleeding with thromboprophylaxis. Recent studies suggest direct oral anticoagulants (DOACs) may provide effective thromboembolism prevention, but concerns regarding bleeding risk, hepatic impairment, and lack of robust data persist. This study investigates thromboprophylaxis practices among UK adult congenital heart disease (ACHD) specialists, focusing on the use of DOACs in Fontan patients.
An electronic survey was distributed to UK National ACHD Consultant Group members from February to March 2023. Based on hypothetical clinical scenarios, the survey collected demographic data, familiarity with DOACs, and preferred thromboprophylaxis strategies. Responses were analysed using descriptive statistics to identify patterns in practice.
There was a maximum response rate of 42%, with 32 respondents participating, primarily consultants from level 1 ACHD centres. Thromboprophylaxis strategies varied significantly: DOACs, warfarin, and aspirin were used with varying frequency, depending on clinical factors, such as arrhythmias, thrombosis history, and patient-specific challenges. While 35% of respondents were comfortable prescribing DOACs, 42% expressed reservations, citing limited evidence and concerns about risks.
This study highlights wide variability in thromboprophylaxis strategies for Fontan patients in the NHS, underscoring significant gaps in evidence. Hepatic considerations, patient-specific challenges, and the lack of DOAC licensing for certain scenarios contribute to the complexity of clinical decision-making. Prospective studies are essential to guide practice, and patient involvement in shared decision-making is critical in the interim.
Introduction
Adults living with a Fontan circulation are at persistently elevated potential risk of both thrombosis and bleeding. The Fontan procedure is a palliative surgical strategy for patients with univentricular congenital heart disease, which reroutes systemic venous return directly to the pulmonary arteries.1 This unique physiology leads to a non-pulsatile, low-pressure pulmonary circulation, which contributes to chronic venous congestion, blood stasis and altered flow dynamics. These factors, alongside endothelial dysfunction and potential coagulation abnormalities, create a prothrombotic environment.2 Increased bleeding risk can arise from Fontan-associated coagulopathy,3 or as a direct result of medications for thromboprophylaxis.
Undertaking randomised-controlled trials (RCTs)to explore the optimal thromboprophylaxis strategy is challenging, due to the heterogeneity and complexity of clinical profiles, and requires studies with multi-centre input, over a long period of observation and significant funding, which is often lacking. Direct oral anticoagulants (DOACs) have become a licensed and guideline-indicated treatment for several conditions, including non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism. Rivaroxaban has recently been approved by the Food and Drug Administration (FDA) for use in children post-Fontan procedure following the UNIVERSE study.4 There have been two meta-analyses5,6 that have scrutinised thromboprophylaxis strategies in patients with a Fontan palliation, both concluded that DOACs may offer superior thromboembolism prevention compared with aspirin or warfarin. The reviews suggest an increased risk of major bleeding with anticoagulation, although there is a lack of consensus on which poses the greater risk – thromboembolism or bleeding. An important limitation of both meta-analyses is the inclusion of data across all ages, with few included studies specifically focusing on the use of DOACs in adults. Since clotting and bleeding mechanisms differ significantly between adults and children, extrapolating data from children to adults may be inappropriate. There are no prospective RCTs in adults directly comparing DOACs and warfarin, but there is increasing recognition of DOACs being a suitable agent in patients with a Fontan, with the American College of Cardiology (ACC) recommending consideration of a DOAC as a potential anticoagulant.7 This study explores prescribing practices for thromboprophylaxis across the UK, focusing on the use of DOACs in adults with a Fontan palliation.
The aim of the study was to investigate practices in antithrombotic strategies among adult congenital heart disease (ACHD) specialists throughout the UK.
Materials and method
An electronic survey was distributed to all ACHD specialists who are members of the National ACHD Consultant Group in the UK during February and March 2023. Recipients were also asked to forward the survey to other colleagues who may not have been directly included. There were at least 77 invited participants. The survey collected basic demographic data, including the respondent’s grade, place of work, and familiarity with DOACs for Fontan patients. Clinical practice variation was assessed with a baseline scenario of an 18-year-old patient with an extracardiac Fontan. Respondents were asked to select their preferred thromboprophylaxis strategy. Treatment options were provided in tick-box format, including aspirin, DOAC, or warfarin, with an option for free-text responses. Several variations of the baseline scenario were included to evaluate how different clinical factors might influence treatment choices. Data were analysed using descriptive statistics to identify patterns and differences in practice.
Results
A total of 32 respondents participated. Based on a minimum of 77 invited participants, this represents a maximum response rate of 42%. The majority of respondents were consultants (31/32). The respondents represented various ACHD centres across the UK, including 28 from nine different level 1 ACHD centres in the UK, three from level 2 centres and one from a level 3 centre.
The preferences for thromboprophylaxis strategies are summarised in table 1. For patients without additional risk factors, practice varied significantly, with DOACs, warfarin, and aspirin being similarly popular. A history of atrial arrhythmia increased the likelihood of recommending anticoagulation instead of antiplatelet therapy. Patients with a history of thrombosis were more likely to be prescribed warfarin, though some clinicians still preferred DOACs. In scenarios involving poor compliance, difficult-to-control INRs (International normalised ratio) or needle phobia, DOACs were more frequently recommended. For patients with menorrhagia, the choice of antithrombotic strategies was broadly similar across the board.
Table 1. Questionnaire responses on choice of thromboprophylaxis strategy
| Scenario | Warfarin n (%) | DOAC n (%) | Aspirin n (%) | Other n (%) |
| An 18-year-old patient with an EC Fontan has reassuring echo features and no history of thrombosis, arrhythmias or bleeding | 9 (29) | 10 (32) | 7 (23) | 5 (16) [1 aspirin or DAPT; 1 aspirin or nil; 2 nil; 1 DAPT] |
| An 18-year-old patient with an EC Fontan and a history of atrial arrhythmias | 17 (55) | 13 (42) | – | 1 (3) [1 warfarin or DOAC] |
| An 18-year old patient with an EC Fontan and a remote history of intra-cardiac clot | 24 (77) | 6 (19) | – | 1 (3) [1 enoxaparin] |
| An 18-year-old patient with an EC Fontan and poor compliance with medications | 9 (29) | 15 (48) | 2 (6) | 5 (16) [1 aspirin or DOAC; 2 aspirin or warfarin; 1 request further information; 1 no answer provided] |
| An 18-year-old patient with an EC Fontan on warfarin and a difficult to control INR | 4 (13) | 24 (77) | – | 3 (10) [1 aspirin or DOAC; 2 no answer provided] |
| An 18-year-old patient with an EC Fontan and severe needle phobia | – | 22 (71) | 1 (3) | 8 (26) [4 aspirin or DOAC; 1 aspirin or DAPT; 1 warfarin or DOAC; 1 aspirin and DOAC; 1 no answer provided] |
| An 18-year-old patient with an EC Fontan and menorrhagia | 10 (32) | 10 (32) | 6 (19) | 5 (16) [1 aspirin or DOAC; 1 aspirin, DOAC or warfarin; 1 warfarin or aspirin; 2 no answer provided] |
| An 18-year-old patient with an EC Fontan with signs of increased liver stiffness on USS/Fibroscan, but normal synthetic function | 13 (42) | 9 (29) | 2 (6) | 7 (23) [4 no answer provided; 1 aspirin or warfarin; 1 warfarin or DOAC; 1 any] |
| An 18-year-old patient with an EC Fontan has elevated liver stiffness on imaging and mildly abnormal liver function tests | 14 (45) | 7 (23) | 2 (6) | 8 (26) [4 no answer provided; 2 warfarin or DOAC; 2 any] |
| Key: EC = extracardiac; DAPT = dual antiplatelet therapy; DOAC = direct oral anticoagulant; INR = International normalised ratio; USS = ultrasound scan | ||||
Table 2. Questionnaire responses on the rationale for not using direct oral anticoagulants (DOACs)
| Rationale for not using DOACs | Frequency, n (%) |
| Not applicable as I use them routinely | 10 (32) |
| Lack of evidence | 18 (58) |
| Lack of licensed indication | 7 (23) |
| Experience of adverse events | 3 (10) |
| Concerns regarding bleeding risk | 8 (26) |
| Concerns regarding thrombotic risk | 12 (39) |
| Concerns regarding side effects | 0 |
| Not used in my institute | 2 (6) |
There were varying levels of respondent comfort with using a DOAC in the survey. Overall, 35% of respondents were ‘very comfortable’ with their use, often using them first line. Meanwhile, 42% of respondents were ‘somewhat comfortable’, but might still opt for alternatives, and 23% of respondents would only use a DOAC in selected cases. The primary reasons for not using a DOAC in this patient cohort are summarised in table 2. The most common reasons were a lack of evidence for their use (58%); concerns over thrombotic risk (39%); bleeding risk (26%); and the absence of a licensed indication (23%).
Discussion
Thromboprophylaxis strategies for patients with Fontan circulation vary widely in the NHS, and this highlights a considerable gap in the current evidence base. Rigorous investigation of anticoagulation choices in this patient population is particularly challenging due to the complexity of influencing factors, such as underlying anatomy, type of Fontan surgery, presence of anatomical dead ends, history of thrombosis or arrhythmias, and ventricular, valvular, renal, and hepatic function.
Evaluating anticoagulation options against warfarin is further complicated by the need to maintain a therapeutic range, which can be difficult for some patients, and may be influenced by the quality of the dosing regimen. Hepatic involvement is common, with Fontan-associated liver disease (FALD) and resultant liver cirrhosis, with or without portal hypertension, and hepatocellular carcinoma (HCC) being of significant concern. Given that certain DOACs, apixaban and rivaroxaban, undergo extensive hepatic metabolism, their use in patients with significant hepatic impairment warrants caution. Although dabigatran and edoxaban rely less on hepatic clearance, manufacturers still advise against their use in cases of severe hepatic impairment. While emerging data suggest a potential role for DOACs in cirrhosis, evidence in advanced liver disease remains sparse.8,9 A recent study10 reported an association between the absence of warfarin and the development of HCC in patients with Fontan circulation; however, the role of DOACs was not investigated, and other studies have not corroborated this finding.11 Some studies suggest that warfarin may have antifibrotic properties and may be favoured by hepatologists, especially in patients with advanced FALD.12 Beyond thrombosis and bleeding risk, variability in clinical practice may be driven by additional factors. For example, the frequent monitoring required for warfarin therapy can disrupt patients’ quality of life, diet, education and employment. The burden can be particularly challenging for patients with needle phobia. While home-based blood-spot testing and remote dosing offer some relief, these challenges remain significant. Finally, DOACs are not licensed in pregnancy, and, therefore, may not be suitable for women of childbearing age who are at risk of, or are planning, pregnancy. However, warfarin at doses of more than 5 mg/day in the first trimester are not recommended,13 and, therefore, consideration must be given to women of childbearing potential requiring anticoagulation.
Limitations
There are some notable limitations to our study. The patient scenarios used in this study were purely hypothetical, with only limited data. More thorough consideration would likely be applied in clinical practice, which may result in different treatment decisions. Additionally, the recently published meta-analyses were conducted shortly before (one month) or shortly after the survey was administered and may influence future practice. Consequently, comfort levels and clinical practices may have evolved since the time of the study and review of the literature. Finally, the relatively small sample size and potential response bias may limit the generalisability of the results, meaning they may not fully represent current UK practice.
Further research is needed to identify the optimal thromboprophylaxis in patients with a Fontan. Given the current uncertainty, it is crucial that patients are actively involved in the decision-making process and that anticoagulation strategies are individualised for each patient. In light of the complexity of some patients, the involvement of other multi-disciplinary team members, such as hepatology and haematology, may be considered.
Key messages
- Optimal thromboprophylaxis strategies in patients with a Fontan palliation are unclear
- Current practice varies significantly among clinicians
- Further research and trials are required in order to establish the optimal thromboprophylaxis strategy
- An individualised patient-specific approach is required
Conflicts of interest
None declared.
Funding
None.
Study approval
As this study was a survey of professional practice that did not involve randomisation, patient interventions, or changes to care pathways, ethical approval was not required.
References
1. Gewillig M. The Fontan circulation. Heart 2005;91:839–46. https://doi.org/10.1136/hrt.2004.051789
2. Van Den Helm S, Sparks CN, Ignjatovic V, Monagle P, Attard C. Increased risk for thromboembolism after Fontan surgery: considerations for thromboprophylaxis. Front Pediatr 2022;10:803408. https://doi.org/10.3389/fped.2022.803408
3. Tomkiewicz-Pajak L, Hoffman P, Trojnarska O, Lipczyńska M, Podolec P, Undas A. Abnormalities in blood coagulation, fibrinolysis, and platelet activation in adult patients after the Fontan procedure. Thorac Cardiovasc Surg 2014;147:1284–90. https://doi.org/10.1016/j.jtcvs.2013.06.011
4. Pina LM, Dong X, Zhang L et al. Rivaroxaban, a direct Factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: rationale and design of a prospective, randomized trial (the UNIVERSE study). Am Heart J 2019;213:97–104. https://doi.org/10.1016/j.ahj.2019.04.009
5. Van den Eynde J, Possner M, Alahdab F et al. Thromboprophylaxis in patients with Fontan circulation. J Am Coll Cardiol 2023;81:374–89. https://doi.org/10.1016/j.jacc.2022.10.037
6. Sethasathien S, Phinyo P, Sittiwangkul R, Silvilairat S. Comparative effectiveness among thromboprophylaxis strategies after the Fontan operation: a systematic review and network meta-analysis. Thromb Res 2024;241:109093. https://doi.org/10.1016/j.thromres.2024.109093
7. Alsaied T, Possner M, Van Den Eynde J, Kreutzer J. Anticoagulation algorithm for Fontan patients. American College of Cardiology, 2023. Available at: https://www.acc.org/Latest-in-Cardiology/Articles/2023/04/05/14/10/Anticoagulation-Algorithm-For-Fontan-Patients
8. Zhao Y, Zhu L, Yang Y, Gao H, Zhang R. Safety of direct oral anticoagulants in patients with liver disease: a systematic review and meta-analysis. Acta Clin Belg 2023;78:234–44. https://doi.org/10.1080/17843286.2022.2108259
9. Huang ZC, Li CQ, Liu XY et al. Efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation and liver disease: a meta-analysis and systematic review. Cardiovasc Drugs Ther 2021;35:1205–15. https://doi.org/10.1007/s10557-020-07065-y
10. Sakamori R, Yamada R, Tahata Y et al. The absence of warfarin treatment and situs inversus are associated with the occurrence of hepatocellular carcinoma after Fontan surgery. J Gastroenterol 2022;57:111–19. https://doi.org/10.1007/s00535-021-01842-8
11. Ohuchi H, Hayama Y, Nakajima K, Kurosaki K, Shiraishi I, Nakai M. Incidence, predictors, and mortality in patients with liver cancer after Fontan operation. J Am Heart Assoc 2021;10:e016617. https://doi.org/10.1161/JAHA.120.016617
12. Oh H, Park HE, Song MS, Kim H, Baek JH. The therapeutic potential of anticoagulation in organ fibrosis. Front Med (Lausanne) 2022;9:866746. https://doi.org/10.3389/fmed.2022.866746
13. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J et al.; ESC Scientific Document Group. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39:3165–241. https://doi.org/10.1093/eurheartj/ehy340
