Author + information
- Gunter Balling, MD, DrMed∗ ()
- Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center, Technical University Munich, Munich, Germany
- ↵∗Reprint requests and correspondence:
Dr. Gunter Balling, Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München (German Heart Center), Lazarettstrasse 36, D 80636 Munich, Germany.
Thrombus formation is a significant cause of morbidity and mortality after Fontan operations. Intracardiac thrombus formation can lead to chronic pulmonary embolism (e.g., from system veins or subpulmonary ventricle) or stroke (e.g., from pulmonary veins or the systemic ventricle). Those “right-sided” embolisms may result in a ventilation/perfusion mismatch or an elevation of pulmonary vascular resistance, both of which may seriously hamper the cavopulmonary circulation. Preventing thromboembolism after the Fontan procedure and the role of a proper prophylaxis remains an ongoing discussion. The published reports are fraught with controversies about prophylactic antiplatelet and/or anticoagulation therapy, with some retrospective reviews supporting antiplatelet therapy, others suggesting that anticoagulants are more effective, and still others discouraging routine anticoagulation.
Marrone et al. (1) performed a systematic review and meta-analysis involving 1,075 patients after Fontan operations, with 220 (20.4%) in the antiplatelet group and 855 (79.5%) in the anticoagulation group. Mean follow-up ranged from 2 to 144 months, and the overall rate of thromboembolism was 5.2%. The meta-analysis demonstrated the safety and efficacy of a therapeutic strategy based on antiplatelet therapy. The study verified that for patients with an extracardiac Fontan, antiplatelet therapy is associated with a rate of early or late thromboembolic events and bleeding similar to that for anticoagulation therapy alone or for a combination with anticoagulation and antiplatelet drugs. Yet, Khairy et al. (2) found the absence of aspirin or warfarin therapy to be a powerful independent predictor of mortality from thromboembolism.
Despite the lack of large, prospective studies with long-term follow-up showing the efficacy of prophylactic therapy, most retrospective studies concluded with a clear recommendation of lifelong routine anticoagulation or antiplatelet therapy in Fontan patients (3,4).
Adults who had been treated by a Fontan operation early in life had significantly reduced platelet numbers but increased basal platelet activity, increased prothrombotic endothelial dysfunction, and evidence of systemic inflammation. A significant proportion of aspirin-treated adults showed aspirin resistance, which might partially explain the ineffectiveness of aspirin in preventing thromboembolic complications (5).
On the other hand, for warfarin therapy, the small therapeutic window remains problematic. To avoid a subtherapeutic international normalized ratio or bleeding with warfarin, there are effective and safe methods for self-monitoring anticoagulation that are especially helpful in children when combined with comprehensive educational support for the parents (6).
The retrospective study by Egbe et al. (7) in this issue of the Journal is an important contribution to this issue. From a large cohort of patients who had undergone a Fontan procedure in a single institution, the investigators selected a subpopulation of 278 patients with a history of atrial arrhythmias over a period of 2 decades. One-half of the patients showed nonspecific symptoms. At the time of diagnosis, actual ongoing atrial arrhythmias were present in 64%. Thrombus was detected on echocardiography and computed tomography or cardiac magnetic resonance scans in 29% of adult patients after a Fontan operation and history of atrial arrhythmia. Right-sided embolism was detected in two-thirds and left-sided embolism in one-third of the events.
Interestingly, in the study presented by Egbe et al. (7), the cohort with a history of atrial arrhythmias was being treated with 2 different regimens for preventing thromboembolism. The majority (65%) received antiplatelet therapy (164 on aspirin, 64 on clopidogrel, and 1 on both) and only 33% were on oral anticoagulation (33 on warfarin alone; 55 on warfarin + aspirin; and 3 were taking a nonvitamin K oral anticoagulant [NOAC]). Unfortunately, one-third of patients on warfarin had subtherapeutic international normalized ratio. Nevertheless, they experienced significantly fewer thromboembolic events than the patients with antiplatelet therapy alone (11% vs. 22%; p = 0.016). Furthermore, the subset of patients with atriapulmonary connections showed the highest thromboembolic risk compared with other more modern forms of Fontan circulation.
When Fontan operations other than total cavopulmonary connection are used, as in the present study (81% atriapulmonary connection), a history of clinically relevant arrhythmias and signs and symptoms of heart failure have been identified as strong prognostic factors of morbidity and mortality, which is hardly surprising. In the literature, the incidence of atrial arrhythmias and Fontan circulation is estimated around or even more than 50%. At 20-year follow-up, overall freedom from tachycardia was estimated to be only 46 ± 12% (8–10). A combination of these factors (Fontan and arrhythmias) was strongly related to the risk of death or transplantation and was far superior to any measure of cardiopulmonary exercise testing in assessing outcome (11). In the study from Varma et al. (12), for example, the patients who received warfarin because of atrial arrhythmias had a zero incidence of clinically silent pulmonary embolism.
This supports expert consensus (13), where patients with a Fontan hemodynamic are considered to have a complex/severe congenital heart disease and, in the presence of atrial arrhythmias, thromboprophylaxis is reasonable, using long-term oral anticoagulation. Regarding the recommendation of more modern anticoagulation drugs, such as NOACs, the expert group found insufficient safety and efficacy data to recommend them in patients after Fontan surgery. Nevertheless, encouraging favorable data on the use of NOACs in adults with congenital heart disease have just recently been published (14), although only a few patients with Fontan circulation were included.
The study from Egbe et al. (7) is an important contribution to the stratification of risks and incidence of thrombotic and embolic complications in adult Fontan patients. We learned that the incidence is especially high in the subpopulation of patients with atrial arrhythmias. Of course, it would be of particular interest to know the incidence in Fontan patients without any atrial arrhythmias, despite the fact that this might be a minority among adults with Fontan circulation. The 2010 European Society of Cardiology guidelines (15) recommended the following with regard to Fontan patients and anticoagulation: right atrial blood stasis and disturbed coagulation may pre-dispose to thrombosis. The potential for subclinical, recurrent pulmonary embolism leading to a rise in pulmonary vascular resistance has led to a recommendation by some for lifelong anticoagulation.
Egbe et al. (7) should be congratulated on their retrospective study and its contributions to this discussion, although the actual data did not allow a general recommendation for anticoagulation therapy in all Fontan patients. However, especially in older Fontan patients with atriapulmonary connections, the prevalence of thrombotic intracardiac structures and/or complications is substantial. Therefore, in my opinion, this patient group should benefit from systemic anticoagulant therapy. To drive the discussion further, the community treating any Fontan-type patients should consider whether the time has come for serial longitudinal transesophageal echocardiography evaluation (16), including asymptomatic patients, at least in the adult population, in order to gain better insights into the thromboembolic risk of all Fontan patients and derive reliable, evidence-based recommendations for an antithrombotic treatment.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Balling has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Khairy P.,
- Fernandes S.M.,
- Mayer J.E. Jr..,
- et al.
- Firdouse M.,
- Agarwal A.,
- Chan A.K.,
- Mondal T.
- Egbe A.C.,
- Connolly H.M.,
- McLeod C.J.,
- et al.
- Pundi K.N.,
- Johnson J.N.,
- Dearani J.A.,
- et al.
- Diller G.P.,
- Giardini A.,
- Dimopoulos K.,
- et al.
- Varma C.,
- Warr M.R.,
- Hendler A.L.,
- Paul N.S.,
- Webb G.D.,
- Therrien J.
- Khairy P.,
- Van Hare G.F.,
- Balaji S.,
- et al.
- Baumgartner H.,
- Bonhoeffer P.,
- De Groot N.M.,
- et al.