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J Thorac Cardiovasc Surg 1998;115:493-498
© 1998 Mosby, Inc.
SURGERY FOR CONGENITAL HEART DISEASE |
This work was supported in part by the Heart and Stroke Foundation of Ontario.
Received for publication August 21, 1997; accepted for publication Sept. 3, 1997. Address for reprints: Maureen Andrew, MD, Hamilton Civic Hospital Research Centre, 711 Concession St., Hamilton, Ontario L9C 3G1, Canada.
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Introduction |
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 Top Introduction References |
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1 Over subsequent years, many modifications of the original procedure have been described, although the basic principle remains the same. 2-5 The Fontan procedure has evolved as the definitive palliative surgical treatment for most heart lesions when a biventricular circulation is not feasible. 6 Central venous and intracardiac thrombosis are a major cause of morbidity and mortality after Fontan procedures. Arterial embolization to the central nervous system resulting in persistent neurologic deficits is also a significant complication of Fontan procedures. Shirai and colleagues in this issue of the Journal describe a retrospective series of 16 patients undergoing extracardiac Fontan procedures. The median follow-up is 13 months, and the incidence of intracardiac thrombosis is 19%. On the basis of these findings, the authors have begun routine antithrombotic prophylaxis with aspirin for 6 months after all Fontan procedures. The usefulness of such a protocol, as the authors point out, remains to be proven.
Prophylactic anticoagulation with warfarin or antiplatelet agents after Fontan procedures is frequently recommended. 7-9 However, no consensus is found in the literature or in routine clinical practice as to the optimal type or duration of anticoagulation. Consequently, a wide variety of prophylactic anticoagulant regimens are currently used. 10
How does one decide on the most appropriate therapy? Any decision about instituting preventive anticoagulation involves a trade-off between benefits (reduced thromboembolism) and toxicity and cost. Clinical recommendations and treatment guidelines should be based on the best available evidence. This is the founding principle of evidence-based medicine. 11 Such an approach begins with a systematic overview followed by a critical assessment of the existing evidence. 12 Assessment of the literature involves analyzing the strength of study designs, the validity of the results obtained within those designs, and the relevance of those results to the wider patient population. 11,13,14 Useful measures of a treatment's value, such as relative risk reduction and the number needed to treat (to avoid one episode of thromboembolism) can then be used to determine clinical recommendations. 12 In other words, one must assess the strength of the evidence, the necessary impact of treatment to warrant its use, and how well the proposed treatment works. 12
A comprehensive review of the literature pertaining to thromboembolism after Fontan procedures reveals no prospective studies or randomized trials. The current literature consists of cross-sectional point surveys (n = 4, however only two directly assessed thromboembolism), retrospective series in which thromboembolism was either the primary outcome measure (n = 9) or one of multiple outcomes (n = 7), and case reports (n = 15). The potential for bias in such observational studies, especially the latter types (multiple outcomes, case reports), is increased. 12-15 Any treatment recommendations based on these studies would be very weak compared with those obtained from prospective randomized trials. 12,16
The incidence of thromboembolism after Fontan procedures is crucial to the appropriateness of prophylactic anticoagulation. Point prevalences for intracardiac thrombosis ranged from 17% to 20% in the cross-sectional surveys 17,18(Table I). Reported incidences of venous thromboembolism and stroke ranged from 3% to 16% and 3% to 19%, respectively, in the studies in which thromboembolism was the primary outcome 6,7,19-25 (Table II) and from 1% to 7% in studies assessing multiple outcomes 1,3,26-32 (Table III).
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33 The most common methods used to detect venous and intracardiac thrombosis were transthoracic and transesophageal echocardiography, followed by angiography. Other diagnostic methods reported included autopsy (11 cases) and reoperation (6 cases). The most common diagnostic methods used to detect stroke were computed tomography, magnetic resonance imaging, angiography, and clinical diagnosis. The two cross-sectional studies compared transesophageal and transthoracic echocardiography for intracardiac thromboembolism. 17,18 Had the point prevalences from these studies been estimated using transthoracic echocardiography, the results would have been 5% and 3% instead of 17% and 20%. Several other publications reported thromboembolism diagnosed by transesophageal echocardiography or angiography that were not detected using transthoracic echocardiography. 6,7,19
In addition to nonstandardized diagnostic tests, many studies assessed only survivors, with no information on mortality. Mean time from Fontan procedure to thromboembolism was at times greater than mean time of follow-up. 6 The incidence of thromboembolism was increased in recent studies compared with earlier studies, reflecting increased survival, longer duration of follow-up, improved diagnostic tests, or increased awareness of the potential for thrombosis. 6 The retrospective nature of the studies, frequent lack of sensitive diagnostic tests, and limited follow-up not only account for variation in reported incidences but also suggest that the reported incidences of thromboembolism after Fontan procedures are minimal estimations.
The timing of thromboembolism after Fontan procedures is important in determining the optimal duration of prophylactic anticoagulation. The exact duration of time from Fontan procedure to thromboembolism could be calculated for 109 events reported in 16 case series 3,7,17,19-31 and 15 case reports. 8-10,32,34-44 Of these 109 cases of thromboembolism, 54 occurred within the first 3 months after the procedure and 55 occurred after 3 months. Two large series that assessed the timing of thromboembolism both concluded that the period of risk extended beyond 3 months after the procedure, 6,7 with a mean time of 6.1 years in one series. 6 Prophylactic anticoagulation for 3 months after Fontan procedures is frequently advocated; however, it is unjustified on the basis of the existing literature.
Identification of predisposing factors for thromboembolism could allow stratification of patients into high- or low-risk groups that require different intensities of prophylactic anticoagulation. A number of authors have analyzed a variety of possible predisposing factors, including demographic and surgical factors (patient age at operation 6; type of Fontan procedure performed, 6,7 including the presence or absence of fenestration 19,20;type of material used for the conduit; use of valved or nonvalved conduits 6) and hemodynamic factors (arrhythmias, 6,19,20 right-to-left shunts, 20 polycythemia, 19and low cardiac output 24). Although some studies claimed statistically significant relationships, predisposing risk factors were not identified with consistency or certainty because of lack of statistical power, use of retrospective data, and incomplete reporting of data. Consequently, no conclusions can be made about the relative contribution of patient demographic, surgical, or hemodynamic factors in causing thromboembolism after Fontan procedures.
Two studies assessed the role of coagulation deficiencies in the etiology of thromboembolism. Both studies had major inadequacies. 31,45 The reference ranges used to determine normal from abnormal were not age specific, and most children labeled as abnormal were in fact normal for age. Case reports with similar findings also used inappropriate reference ranges, whereas cases reporting normal coagulation factors did not. 6,20,25,37 No accurate data implicate abnormalities of the coagulation system in thromboembolism after Fontan procedures.
All episodes of thromboembolism in the series by Shirai and colleagues were detected on routine transthoracic echocardiographic screening of asymptomatic patients. Warfarin therapy was begun and the patients remained well, although the duration of follow-up was not stated. Routine evaluation with transthoracic echocardiography leading to the detection and treatment of asymptomatic thrombi has previously been reported to improve outcome and reduce the incidence of stroke. 6 However, other cases are reported in which subsequent stroke was not prevented. 17,19 Prospective studies are required to confirm the usefulness of routine screening, in particular with a sensitive test such as transesophageal echocardiography. 46,47
The management of thromboembolism after Fontan procedures is also controversial. Literature on the management and outcome of thromboembolism was scarce and often poorly documented (Table IV). Therapeutic options include surgical embolectomy, with or without further surgical modifications of the intracardiac anatomy; thrombolytic therapy; and anticoagulation therapy. Total resolution of thrombosis was achieved in only 48% of cases. Death occurred in 25% despite aggressive treatment.* Many children do not survive long enough to be given effective antithrombotic treatment. 38
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3 The target international normalized ratio, which reflects the level of anticoagulation, was not stated. In total, from all other case series and reports in the literature, only 16 patients received prophylactic anticoagulation therapy with either warfarin (n = 12), aspirin (n = 3), or heparin (n = 1). 6,7,10,17,19,20,25,35 The rationale for prophylaxis in these particular patients was the presence of fenestration (n = 7), previous thrombosis (n = 2), atrial fibrillation (n = 1), and immobility (n = 1). No rationale was given for a further five cases. Of the 12 patients who received warfarin (target international normalized ratios not stated), five had thromboembolism during or after the prophylactic therapy. In one patient warfarin was discontinued because of bleeding and a subsequent thromboembolus occurred. 35 The three patients given prophylactic aspirin and one patient given heparin all had thromboemboli while receiving prophylactic therapy. In summary, the usefulness of prophylactic anticoagulation therapy remains to be proven. Virtually no information regarding the safety and efficacy of prophylactic anticoagulation with oral anticoagulants or antiplatelet agents exists.
The current study by Shirai and colleagues is useful because it reaffirms the high risk of thromboembolism after Fontan procedures. With increased follow-up and using a more sensitive diagnostic method like transesophageal echocardiography, the incidence of thromboembolism after Fontan procedures is likely greater than 20%. In combination with the reported poor outcome of thromboembolism, prophylaxis seems logical. The optimal type and duration of any such therapy is unknown. Returning to our framework of evidence-based medicine, we can find little evidence documenting the benefits or risks of routine prophylaxis. Measures such as relative risk and number needed to treat cannot be applied because the appropriate studies have not been done. Current practices can only be viewed as opinions based, at best, on theory and personal experiences. As we approach the next millennium, this level of evidence is insufficient grounds for management of an important issue that has remained unresolved for 25 years. By design, retrospective case series like that of Shirai and colleagues and those published previously cannot resolve this issue. 15 These questions can only be answered in well-controlled, prospective studies. 13,14 Single institutions are unlikely to successfully complete such studies. Multicenter randomized controlled trials comparing prophylactic antiplatelet and anticoagulation therapies are urgently required to provide rational scientific guidelines for the future management of Fontan procedures in children.
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Footnotes |
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*6,7,10,17-19,22,23,25-27,32,34-36,39-44 
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References |
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