Effect of Aspirin and warfarin therapy on thromboembolic events in patients with univentricular hearts and Fontan palliation

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Abstract

Background

Patients with univentricular hearts and Fontan palliation are at risk for thromboembolic complications. While aspirin and warfarin therapies are currently the mainstay of prophylaxis, controversy exists as to the optimal prevention strategy.

Methods

A cohort study was conducted on the New England registry of patients born in 1985 or earlier with Fontan surgery at Boston Children's Hospital, in order to assess and compare the effect of prophylactic aspirin and warfarin on incident thromboembolic events.

Results

A total of 210 qualifying patients (49% male) underwent Fontan surgery at a median age of 8.5 years: 48.6% had a right atrium to pulmonary artery anastomosis, 11% a right atrium to right ventricle conduit, 38.6% a lateral tunnel, and 1.9% an extracardiac conduit. No thromboembolic prophylaxis was prescribed to 50.0%, whereas 24.3% received aspirin, and 25.7% warfarin. In multivariate analyses, lack of aspirin or warfarin was associated with a significantly higher thromboembolic event rate when compared to therapy with either [hazard ratio 8.5, 95% confidence interval (3.6–19.9), P < 0.001], with no difference between the two treatment strategies (P = 0.768). Twenty-year freedom from thromboemboli was 86% versus 52% in patients with and without thromboprophylaxis, respectively. Other factors independently associated with thromboemboli were a low post-operative cardiac index [hazard ratio 2.6, 95% confidence interval (1.2, 5.9)] and atrial fibrillation or flutter [hazard ratio 3.1, 95% confidence interval (1.2, 8.0)].

Conclusions

Prophylaxis with either aspirin or warfarin was associated with a significantly lower rate of incident thromboembolic events following Fontan palliation, with no difference between the two therapies.

Introduction

The Fontan procedure encompasses a family of related operations [1], [2], [3], [4], [5], [6], [7] with the common goal of palliating the “univentricular heart” [6] by rerouting systemic venous return directly to the pulmonary arterial circulation. Outcomes have improved considerably over the last 25 years such that patients are now increasingly surviving into adulthood, exposing them to various longer-term complications, including heart failure, arrhythmias, and thrombosis [4], [5], [6], [8], [9], [10], [11], [12]. Thromboembolic complications are a well-recognized source of morbidity [13], [14], [15] and mortality [9] in patients with Fontan physiology. Thromboembolic death may occur suddenly or be preceded by other thromboembolic events, which may or may not be symptomatic [16], [17], [18]. As many as 25% of clinical thromboembolic events in patients with Fontan surgery are fatal [16], [18]. While the prevention of thromboembolic events is a desirable clinical goal, controversy exists as to the optimal prophylaxis strategy [16], [18], [19], [20], [21], [22], [23], [24], [25]. Given the paucity of evidence regarding prophylactic therapy with newer antithrombotic regimens in this patient population [24], aspirin (ASA) or warfarin remain the mainstay of antiplatelet or anticoagulant therapy. We, therefore, sought to evaluate and compare the effect of prophylactic ASA and warfarin on incident thromboembolic events in a cohort of patients with Fontan palliation.

Section snippets

Study cohort

The New England Fontan registry included all patients who lived in the New England area, were born before 1985, and had Fontan surgery between April 1973 and July 1991 at Boston Children's Hospital. Details of this cohort have been previously described [9], [10]. Patients with surgery limited to cavopulmonary shunts were ineligible, including those with an interrupted inferior vena cava and azygos extension to a superior vena cava who underwent a bidirectional cavopulmonary shunt. For the

Baseline characteristics

A total of 210 patients, 49.0% of whom were male, underwent a first Fontan surgery at a median age of 8.5 (IQR 4.8, 15.2) years. Seventy-two (34.3%) patients had tricuspid atresia, 51 (24.3%) a double-inlet left ventricle, and 4 (1.9%) hypoplastic left heart syndrome. The single ventricle was morphologically left in 70.5%. The type of first Fontan procedure was a RA to PA connection in 102 (48.6%) patients, RA to RV conduit in 23 (11.0%), lateral tunnel in 81 (38.6%), and extracardiac tunnel in

Discussion

The key findings of this analysis from the New England Fontan registry are that 1) prophylaxis with either aspirin or warfarin is associated with a significantly lower incident thromboembolic event rate; 2) no signal favored one therapy over the other; 3) the residual risk of thromboemboli remains substantial despite ASA or warfarin therapy; and 4) other factors associated with a higher risk of thromboembolic events include a low post-operative cardiac index and a history of atrial fibrillation

Conclusion

A high rate of incident thromboembolic events was observed in the New England cohort of Fontan patients followed for over 14 years. Prophylactic therapy with ASA or warfarin was associated with a significant reduction in the thromboembolic event rate, with the two treatment strategies yielding similar outcomes. Despite protective therapy, patients remained at substantial residual risk for thromboembolic events. Adequately powered prospective trials comparing these and other prophylactic

Statement of authorship

The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Conflict of interest disclosures

Dr. Khairy has received research support for an investigator-initiated grant from Boehringer Ingelheim.

Acknowledgement

Drs. Susan Fernandes, Michael Landzberg, and Paul Khairy received research support from the Dunlevie Foundation.

References (34)

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