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Dr. Carl L. Backer, Cardiovascular-Thoracic Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue Box 22, Chicago, Illinois 60611-2605
The old adage, “an apple a day keeps the doctor away,” when altered to “an aspirin a day keeps the doctor away” appears to be especially appropriate for patients who have had a Fontan operation. The group from the Hospital for Sick Children has in this issue of the Journal reported a secondary analysis of an important trial of thromboprophylaxis after the Fontan procedure (1). In this secondary analysis the Toronto group further investigated the unique and important data set accumulated in their previous study, “A Multicenter, Randomized Trial Comparing Heparin/Warfarin and Acetylsalicylic Acid as Primary Thromboprophylaxis for 2 Years After the Fontan Procedure in Children” (2).
Any surgeon who performs the Fontan procedure has encountered at some point in his or her career a thrombotic post-operative complication. These patients appear to be at risk of thromboembolism for many reasons: a known hypercoagulable state, the use of intracardiac prosthetic materials, atrial arrhythmias, intracardiac shunting (fenestration), low-flow states, and stasis in the venous pathways. The original paper published by the Toronto group randomized patients to receive either aspirin (5 mg/kg/day) or warfarin with a target international normalized ratio of 2.0 to 3.0 (2). A total of 111 eligible patients were randomized in a prospective fashion. The incidence of thrombosis was essentially identical between the 2 groups and major bleeding occurred in only 1 patient in each group. The conclusion of this randomized prospective trial was that there was no significant difference between aspirin therapy and warfarin as primary thromboprophylaxis in the first 2 years following the Fontan procedure. The thrombosis incidence was still high at 19% in both groups, which the authors suggested means there is still room for improvement in the care of these patients.
The current review delves deeper into the potential areas for improvement that might be brought to the forefront from the original study group. This secondary analysis of a unique and important dataset revealed the following important factors. First, the hazard of thrombosis was noted to be highest immediately after the Fontan procedure, but there was also a gradual increase in risk during late follow-up. The higher incidence of thromboembolism in the first several weeks and months following the Fontan procedure has been previously demonstrated and has some logical explanations. The delayed hazard, however, seems somewhat counterintuitive as one would think that after several years there would be less chance of thrombosis formation at suture lines and along prosthetic pathways which presumably would become covered with neointima over a period of time. The inference here is that lifetime anticoagulation of some sort is probably necessary.
The most striking and important new information, though, appears to be the fact that patients who were on a warfarin dose that was subtherapeutic actually had a significantly increased incidence of thrombosis issues compared with patients who were maintained on either carefully controlled warfarin therapy or the aspirin therapy. It is well known to clinicians that the difficulties of managing warfarin therapy in children are not insignificant. Missing doses, changing diets, and intercurrent illnesses all affect the international normalized ratio levels. The ease of aspirin administration by contrast and the attendant higher compliance presumably accounts for the improved outcomes.
There were several other findings with the secondary review regarding the factors associated with a higher risk of thrombosis: 1) the diagnosis of pulmonary atresia with intact ventricular septum; 2) pulmonary artery distortion; 3) higher pre-operative unconjugated bilirubin; 4) the use of central venous lines for >10 days or until hospital discharge; and 5) a lower FiO2 24 h after the procedure. Pulmonary artery distortion is understandable, as is prolonged central line use. The others are not necessarily intuitive.
Other surgeons have previously suggested that aspirin therapy may be a better strategy after the Fontan procedure than the use of warfarin. Marshall Jacobs published a study in 2002, “Fontan's Operation: Is Aspirin Enough? Is Coumadin Too Much?” (3). He was actually quite prescient in his analysis as many of the points demonstrated by this secondary analysis were noted in his review. His conclusion was that “low dose aspirin can be used safely in young patients with Fontan connections. In the intermediate follow-up the strategy of aspirin therapy was effective in preventing thromboembolic complications. The routine use of more aggressive anticoagulation such as Coumadin may be unwarranted” (3). Those conclusions from a very experienced Fontan surgeon were nearly identical to those of the recent randomized prospective study!
It may be that improvements in surgical techniques (i.e., the use of a bidirectional superior cavopulmonary anastomosis and the extracardiac Fontan) will decrease the incidence of thromboembolic events. These operations are associated with more laminar blood flow and less blind cul-de-sacs than the previously described atriopulmonary and lateral tunnel Fontan operations. These operations avoid stasis in the venous pathways and may decrease atrial arrhythmias that are known to contribute to thrombus formation. Other risk factors such as the need for bilateral bidirectional cavopulmonary anastomosis may not be amenable to modification.
I congratulate the Toronto group on enhancing our understanding of the important issue of thrombotic complications after the Fontan operation. Their ability to organize and conduct a randomized trial of thromboprophylaxis is a notable event in pediatric cardiac surgery. The secondary analysis has improved our understanding of how to care for and prevent thrombotic complications in this unique patient population.
An apple a day keeps the doctor away. In Fontan patients an aspirin a day seems to keep the clots away.
Dr. Backer has reported that he has no relationships relevant to the contents of this paper to disclose.
↵⁎ 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.
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