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Ann Thorac Surg 2002;74:556-562
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Thromboembolic complications after Fontan procedures: comparison of different therapeutic approaches

^a Department of Thoracic and Cardiovascular Surgery, RWTH University Hospital, Aachen, Germany
^b Medical Clinic I, RWTH University Hospital, Aachen, Germany
^c Department of Pediatric Cardiology, Rheinisch-Westfälische Technische Hochschule University Hospital, Aachen, Germany

Accepted for publication April 10, 2002.

* Address reprint requests to Dr Seipelt, Division of Cardiovascular-Thoracic Surgery, M/C #22, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614, USA
e-mail: rseipelt{at}childrensmemorial.org

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Although patients after Fontan procedure have a high incidence of thromboembolic complications, anticoagulant therapy is not handled uniformly. We analyzed the frequency and clinical relevance of thromboembolism after Fontan procedure and compared different therapeutic approaches.

Methods. From 1986 to 1998, 101 patients (mean age, 7.3 ± 8.1 years) underwent Fontan type procedure (modified Fontan, n = 40; total cavopulmonary connection, n = 61). In 85 of 87 survivors, transthoracic echocardiography was performed; and in 31 transesophageal echocardiography and/or angiography was performed. Mean follow-up was 5.7 ± 3.5 years. Three groups with different anticoagulant regimen were compared: group I without medication (n = 45), group II with acetylsalicylic acid therapy (n = 14) and group III with Coumadin (n = 26).

Results. Thromboembolic events occurred in 13 of 85 patients (15.3%; 3.3 events/100 patient-years). Type of operation as well as other known risk factors had no influence on the rate of thromboembolism. Within the first postoperative year, seven of 13 events occurred. A second peak developed beyond 10 years of follow-up. Patients benefit significantly from Coumadin compared with those who did not receive any medication, with similar results in the entire population and the subgroup of patients with total cavopulmonary connection (log-rank, p = 0.031 and p = 0.033, respectively). With 4.2 events/100 patient-years, the cumulative event rate was substantially higher in group I than with 1.6 in group II and with 1.1 in group III. No relevant bleeding complications occurred.

Conclusions. Thromboembolism is frequent after Fontan procedure, with a peak during the first postoperative year and another peak beyond 10 years of follow-up. Coumadin is the most effective prophylactic therapy in preventing thromboembolism. Therefore, we suggest initial oral anticoagulation therapy in patients with Fontan type operation.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The Fontan procedure was first described by Francis Fontan in 1971 [1]. It is currently, in modified form, a well-established definitive surgical palliation for patients with complex cardiac malformations, in cases in which biventricular circulation cannot be achieved [2, 3]. Among various modifications, a significant alteration of the surgical technique was introduced by de Leval and associates [4] in 1988, when they described the total cavopulmonary connection. Over the last decade, hospital mortality has decreased substantially; therefore, late mortality and, especially, late morbidity are now of greater interest. Besides arrhythmias, dysfunction of the systemic ventricle and protein losing enteropathy, thromboembolic complications have a major impact on long-term prognosis [5–8]. Mortality after thromboembolic events in Fontan patients has been reported to be as high as 25% [7]. This high mortality is explained by the fact that any increase of pulmonary vascular resistance leads to deleterious hemodynamic impairment. Apart from venous thromboembolic complications, stroke or arterial embolization have been described in 3% to 19% of all patients [6, 8–10].

Despite the documented frequency and clinical impact of thromboembolic complications, no consensus is found in the literature regarding anticoagulation practices regarding prophylaxis, methods (ie, Coumadin vs antiplatelet agents), or duration of therapy [7, 11, 12]. The aim of the present study was to analyze retrospectively the frequency, time course, clinical relevance, and origin of thromboembolic complications after Fontan-type surgery. Different methods of anticoagulation for prophylaxis were compared for the entire population and for the subgroup of patients who underwent the currently favored total cavopulmonary connection (TCPC).

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Between January 1986 and December 1998, 101 patients (55 male, mean age: 7.3 ± 8.1 years) underwent modified Fontan procedure for various types of univentricular heart conditions. Preoperative morphologic diagnoses included tricuspid atresia (n = 53), double inlet ventricle (n = 25), and complex malformations (n = 23). The group of patients with complex malformations consisted mainly of patients with criss-cross heart (n = 5), complex forms of congenitally corrected transposition of the great arteries (n = 4), or atrial isomerism (n = 4).

Operative technique
Two different operative techniques were used to direct the systemic venous return to the pulmonary arteries. An anastomosis between the roof of the right atrium and the pulmonary artery (modified Fontan procedure) was performed in 40 patients. In 26 of these patients, the anastomosis was created with autologous atrial tissue only. In the remaining 14 patients, atrial tissue was not sufficient, and a Gore-Tex patch (W. L. Gore & Associates, Flagstaff, AZ) had to be added. Fenestration was created surgically in 1 patient to allow decompression of the systemic venous atrium. Starting in 1991, the concept of modified Fontan has changed in favor of TCPC, usually carried out by creating an intraatrial tunnel to conduct inferior vena cava blood to the superior vena cava orifice. In 27 of 61 patients with TCPC, the intraatrial tunnel could be created with autologous tissue only. A fenestration was performed in 12 of 61 patients.

Anticoagulation regimen
Until October 1995, patients with Fontan procedure received either no prophylactic medication or antiplatelet therapy in the postoperative period. Only in 1 patient with a history of deep venous thrombosis was Coumadin (Du Pont Pharmaceuticals, Wilmington, DE) therapy started. After October 1995, we started using intravenous heparin therapy immediately after operation. Then all except 2 patients received Coumadin early postoperatively before hospital discharge. Two patients were placed on acetylsalicylic acid (ASA) only, as their parents declined Coumadin therapy. Because of the initial anticoagulant regimen, patients were divided into three groups: patients without any medical prophylaxis (group I, n = 45); patients treated with ASA at a dose of 2 to 3 mg/kg/d (group II, n = 14); and patients with Coumadin therapy (target international normalized ratio [INR] between 2.2 and 2.7; group III, n = 26).

Follow-up
Follow-up included clinical examination, electrocardiography, and transthoracic echocardiography (TTE) (Agilent Sonos 5500, Andover, MA) once per year. In addition, transesophageal echocardiography (TEE) was performed in 31 patients. Cardiac catheterization was occasionally performed to evaluate the hemodynamic situation of the patient. Follow-up information was available in 85 of the 87 hospital survivors. The mean follow-up for the entire population was 5.7 ± 3.5 years (range, 10 months to 15 years).

Statistical analysis
Statistical analysis was performed with the Statistical Package for the Social Sciences (version 10.0; SPSS Institute, Chicago, IL). Data are expressed as mean ± standard deviation unless otherwise indicated. Differences between groups were determined using ², Fisher’s exact, and unpaired Student’s t tests. Multiple logistic regression analysis was performed to identify predictors of thromboembolic events. The Kaplan-Meier method was used to estimate event-free probabilities. Values of p less than 0.05 were considered to be statistically significant. Thromboembolic events were analyzed for the study population and for the three prophylactic groups separately. When comparing the three prophylactic approaches, follow-up was limited to the duration of each patient‘s initial prophylactic approach, and periods after change of therapy were excluded. Comparison of the groups was performed after 3 and 5 years using the log-rank test. Beyond a follow-up period of 5 years, a comparison was not meaningful because of the small number of patients in groups II and III.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Outcome
Overall hospital mortality was 13.9% (14 of 101 patients), but was substantially lower (4%, 2 patients) in the last 50 patients. None of the early deaths was caused by thromboembolic complications. Of four late deaths, in one an acute pulmonary artery embolism was the cause 41 months after TCPC. Overall survival was 85% at 1 year, 82% at 5 years, and 79% at 10 years, respectively. Clinical condition was excellent or good in 94% and reduced in 6% at last follow-up.

Thromboembolic events
Thromboembolic events or thrombus formation were detected in 13 of 85 hospital survivors (15.3%), for an overall rate of 3.3 events per 100 patient-years.

Eight patients had a clinical episode of thromboembolism (symptomatic thrombus) (Table 1). Two patients suffered from stroke with left-sided hemiplegia. The postevent cardiac catheterization of the normal contracting systemic ventricle failed to detect thrombi, but revealed a residual pulmonary artery trunk or a rudimentary, previously subpulmonary ventricle in both patients. Both patients did not have a fenestration. Symptomatic events in the venous circulation included a 24-year-old women with erysipelas and severe protein losing enteropathy. She experienced extensive superior vena cava thrombosis originating at a central venous line inserted for albumin substitution and died after pulmonary artery embolism despite Coumadin therapy. Five months postoperatively and 2 months after withdrawal of Coumadin therapy, a 32-year-old woman experienced pulmonary embolism of the right middle and lower lobe. After resumption of anticoagulant therapy, she recovered without persistent perfusion defects or elevated pressure in the venous circulation. In another patient, a symptomatic venous thrombosis of the innominate vein resistant to thrombolytic therapy led to a long-standing chylothorax. Two patients with excessively enlarged right atrium developed atrial flutter and life-threatening right atrium-pulmonary artery conduit thrombosis in 1 case and a mobile right atrial thrombosis obstructing the pulmonary artery anastomosis in the other, necessitating urgent operation with conversion to total cavopulmonary connection more than 10 years after modified Fontan operation. Both patients were doing well at last follow-up 12 and 18 months after the event. One patient suffered from atrial flutter 14.5 years after modified Fontan operation. A thrombus at the lateral portion of the enlarged right atrium was revealed with TEE, and the patient received heparin and amiodarone. On TEE before discharge, the thrombus had resolved. The patient was discharged on a regimen of Coumadin and was doing well 8 months thereafter.

View larger version (8K): [in this window] [in a new window]   Fig 1. Freedom from thromboembolism in 85 patients with modified Fontan operation. Data in parentheses indicate numbers of patients at risk.

Thromboembolic events under different anticoagulant regimen
The majority of thromboembolic events (n = 10) occurred during follow-up without antithrombotic prophylaxis (group I). The ASA medication (group II) did not prevent systemic embolization in 1 child. One patient had a pulmonary artery embolism despite adequate Coumadin therapy (group III). Comparison of the three groups with regard to thromboembolic events and possible risk factors are shown in Table 3. The cumulative event rate in group I was 4.2 events/100 patient-years, which is 3.8 times higher than 1.1/100 patient-years in group III. Group II had an intermediate rate of thromboembolic events with 1.6 events/100 patient-years. There were no relevant bleeding complications or other severe side effects of antithrombotic treatment in both groups II and III. Thromboembolic event-free survival with regard to the initial anticoagulant regimen is depicted in Figure 2. Up to the third postoperative year, patients benefitted significantly from Coumadin compared with patients in group I (p = 0.031 at the third postoperative year), and showed a tendency toward better event-free survival compared with patients in (p = 0.17). Thereafter, although not statistically significant, possibly because of the small absolute number of patients and events, there was a tendency in favor of Coumadin prophylaxis than without medication (p = 0.12 at 5 years).

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot for the three initial prophylactic approaches (n= 85): patients with Coumadin therapy (boldface solid line), with acetylsalicylic acid (broken line), and without anticoagulant prophylaxis (solid line). Data in parentheses indicate numbers of patients at risk. Log-rank test between Coumadin and no medication: p = 0.031 after 3 years and p = 0.12 after 5 years. Log-rank test between Coumadin and acetylsalicylic acid: p = 0.17 after 3 years and p = 0.67 after 5 years.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Thrombotic and thromboembolic complications after Fontan-type procedures are a common and serious problem. In the present study, the incidence during long-term follow-up was 13 of 85 consecutive patients (15.3%; 3.3 events/100 patient years). This is similar to most other recent studies, which have reported a 10% to 20% prevalence of thromboembolic complications in this patient population [6–8, 11, 12].

Of all patients with thrombus formation in our study, 60% experienced a symptomatic event, whereas asymptomatic thrombus was found by chance in the others (mostly detected only by means of TEE). In the past, TEE has been proved to be superior to TTE for the diagnosis of thrombus formation in Fontan patients [13, 14]. Thus, our study (as most previous studies) may underestimate the true frequency of asymptomatic thrombus formation because TEE was not used systematically. This is mainly due to the fact that the majority of patients were children who required in a high percentage general anesthesia to undergo TEE. Therefore, TEE was performed in selected patients only.

Risk factors for thromboembolism
In 1986, Matthews and coworkers [10], in a small study group, already recognized that Fontan patients are at risk for postoperative cerebrovascular events. Three of 16 patients (19%) who survived the early postoperative period experienced stroke within 3 months after surgery. The substantially lower prevalence of stroke of 2.3% in the present study was similar to a rate of 2.6% reported in a large study with 645 patients [9]. Systemic embolic complications require either a residual right-to-left shunt at the atrial level with paradoxical embolism of primarily venous thrombi or low-flow areas in connection to the systemic ventricle, with a potential for thrombus formation and its subsequent embolization. In recent studies, thrombus formation in the residual pulmonary artery trunk was detected in 4% to 6% of cases [11, 15]. Thrombotic material may reach the systemic circulation if pulmonary valve regurgitation is present. Similarly, angiography of the systemic ventricle revealed the potential source of postoperative embolic stroke in our 2 patients: long-standing opacification of the residual pulmonary artery trunk, indicating low-flow areas. In addition, asymptomatic thrombus formation in the residual pulmonary artery trunk was found in 3 other patients. As a consequence finding a persistent flow in the residual pulmonary artery trunk, oversewing or even excision of the pulmonary valve have been proposed to prevent from systemic embolization out of this area [11, 15, 16].

Other potential risk factors for venous and systemic thrombosis or embolic events after Fontan-type procedures have been described in literature. Morphologic and functional factors such as patch material used for the lateral tunnel, fenestration, excessive right atrial enlargement, severe dysfunction of the systemic ventricle, as well as supraventricular tachycardia or atrial flutter may promote thrombus formation in the right or left atrium [6, 8, 9, 17]. None of these factors could be identified in our study. As in recent studies [8, 18], the type of operation (modified Fontan, TCPC) had no influence on the actuarial freedom from thrombus formation.

Coagulation abnormalities predisposing for thromboembolic events have been demonstrated in patients after Fontan-type procedures. It was recommended that these patients should be treated with anticoagulation [19, 20]. In-dwelling central venous catheters were a possible source for thrombus formation. Therefore, it was our policy throughout the study to remove the central venous catheter as soon as possible.

Time course of thromboembolic events
Rosenthal and colleagues [8] observed a fairly constant risk for thromboembolism up to 14 years after surgery. In contrast, the majority of events in our study occurred within the first postoperative year, as also reported by others [6, 10, 11]. After 3.5 years a plateau was reached followed by a second peak beyond 10 years of follow-up.

The number of patients who survive more than 10 years after Fontan procedure will increase constantly in the near future. Therefore, therapeutic and prophylactic concepts to avoid thromboembolic complications and arrhythmias in patients at special risk are needed. Recently, the conversion from Fontan connection to intracardiac TCPC has been described as a therapeutic approach in patients with excessive enlargement of the venous atrium to improve blood flow characteristics and to prevent from thrombus formation and atrial arrhythmias [21, 22]. In 2 of our patients, this conversion has been performed successfully. Another therapeutic option, used in one of our patients, could be the treatment with antiarrhythmic medication and anticoagulant therapy. However, the best management for these patients is still unknown, and further studies investigating long-term outcome are urgently required to find a consensus on type and duration of prophylactic anticoagulant therapy.

Prophylactic antithrombotic therapy
Prophylactic anticoagulation therapy is frequently recommended [11, 12, 14, 20], but at this time there is no prospective study investigating different anticoagulation regimen in Fontan patients. There are several studies and case reports on the value of anticoagulant prophylaxis in Fontan patients. Nevertheless, systemic or venous thromboembolic events have been reported even during ASA or Coumadin therapy in selective cases [14, 18]. However, all of these studies did not compare different therapeutic approaches. Because the therapeutic regimen in our center changed in 1995, we were able to compare different prophylactic approaches over a follow-up period of 5 years postoperatively. Since October 1995, all except 2 of our patients received heparin immediately after operation, followed by Coumadin. We kept the INR target level between 2.2 and 2.7. When comparing the different therapeutic approaches in our entire population, patients with Coumadin were shown to have significantly fewer thromboembolic complications up to the third year when compared to patients without medication. Thereafter, we saw a tendency in favor of Coumadin prophylaxis as the most effective regimen. The cumulative thromboembolic event rate was approximately 4 times higher in patients without medication than with Coumadin. Patients with ASA medication had an intermediate state with a higher rate than with Coumadin, but a lower rate than without medication. Because the modified Fontan procedure has now been abandoned by most surgeons, we consequently compared the different therapeutic approaches in the subgroup of patients with TCPC. Hereby, we eliminated the possible interaction of duration of follow-up and type of operation on our results. Patients benefit significantly from Coumadin compared with no medication. However, the absolute number of thromboembolic events in general, and of patients with ASA medication, is very limited, and constitutes the major limitation of this study. The potential benefit of ASA compared with no medication, and its role in relation to Coumadin, must be reproduced in a larger patient sample as part of a multicenter clinical trial. So far, we believe that our data support the concept of early postoperative anticoagulation using heparin followed by oral Coumadin therapy after Fontan-type surgery. The benefit of Coumadin therapy must, of course, be weighed against its risk. In recent studies, the risk of bleeding complications in children with mechanical valves and long-term Coumadin therapy is known to be within a range of 0.8 to 4.0 events/100 patient-years, depending on and increasing with the target INR [23, 24]. Thus, it is even more important to quantify exactly the benefit of anticoagulant therapy in a higher number of children after Fontan procedure. Furthermore, no information on the optimal target INR is available.

In conclusion, thromboembolic events are commonly observed after Fontan-type procedures. In our patient population, thromboembolic events were detected in 13 of 85 hospital survivors, with a peak each during the first postoperative year and beyond 10 years of follow-up. When comparing different anticoagulant regimens, Coumadin was the most effective prophylactic therapy for preventing thromboembolism. Therefore, we suggest initial oral anticoagulation in patients undergoing Fontan-type operations.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ralf G. Seipelt Jaime F. Vazquez-Jimenez Bruno J. Messmer Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seipelt, R. G. Articles by Mühler, E. G. Search for Related Content PubMed PubMed Citation Articles by Seipelt, R. G. Articles by Mühler, E. G. Related Collections Congenital - cyanotic