THEMED ARTICLE y Thrombosis
Editorial
Thrombosis in congenital heart disease Expert Rev. Cardiovasc. Ther. 11(12), 1579–1582 (2013)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
Paul Khairy Montreal Heart Institute Adult Congenital Center, Universite´ de Montre´al, Montreal, QC, Canada [email protected]
“While results of clinical trials in patients with atrial fibrillation or flutter at large are often extrapolated, there is a scarcity of data regarding indications and selection of antiplatelet versus antithrombotic agents, therapeutic doses and targets, bleeding complications and efficacy outcomes specific to congenital heart disease.” Thrombosis in congenital heart disease
Thromboemboli are a well-recognized source of morbidity and mortality in patients with congenital heart disease, with an overall prevalence estimated to be 10 to 100-fold higher than agematched controls [1]. The varied pathophysiology of thrombosis in the setting of congenital heart disease reflects diverse predisposing substrates and the heterogeneous patient population. For example, it has long been suspected that passage of thromboemboli from the right to left atrium across a patent foramen ovale, a remnant of the fetal circulation present in approximately 25% of the population, is implicated in the pathophysiology of cryptogenic stroke. Intracardiac leads for cardiac implantable devices are associated with a higher incidence of systemic thromboemboli in patients with patent foramen ovale [2] and other intracardiac shunts [3]. In addition to systemic thromboemboli via right to left shunts, patients with cyanotic heart disease may develop in situ thrombus in cerebral arteries, intracranial dural sinuses and cerebral veins. Hypercoagulable states associated with surgery and pregnancy, thrombosis secondary to intravascular lines and leads and prosthetic valves are also common in congenital heart disease. Moreover, Eisenmenger physiology, endocarditis and catheter interventions, such as balloon atrial septostomy, have been linked to stroke [1,4]. Other forms of
congenital heart disease may be associated with risk factors for premature atherosclerosis, such as a sedentary lifestyle (e.g., complex congenital heart disease) and hypertension (e.g., aortic coarctation). Among the two most prevalent subgroups of patients with congenital heart disease at risk for thromboembolic events are those with Fontan palliation and atrial tachyarrhythmias. Fontan palliation
Most patients with single ventricle physiology are managed by staged surgery in view of Fontan palliation. Fontan procedures are typically completed between 1.5 and 4 years of age and consist of directing systemic venous return to the pulmonary artery, often bypassing a right ventricle. Since first described in 1971, several modifications and adaptations have been proposed. While the classic Fontan that involved a valved conduit between the right atrium and pulmonary artery is now obsolete, the subsequent generation (the so-called modified Fontan) consisted of a direct anastomosis of the right atrium to a divided pulmonary artery. De Leval later pioneered a total cavopulmonary connection Fontan consisting of an end-toside anastomosis of the superior vena cava to the undivided right pulmonary artery and an intraatrial tunnel that uses a prosthetic patch to direct inferior vena caval flow to the pulmonary artery [5]. Another iteration of the Fontan involves an extracardiac conduit to channel
KEYWORDS: arrhythmia • congenital heart disease • Fontan • stroke • thromboemboli • thrombosis
www.expert-reviews.com
10.1586/14779072.2013.854703
2013 Informa UK Ltd
ISSN 1477-9072
1579
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
Editorial
Khairy
inferior vena caval flow to the pulmonary artery. While Fontan surgery successfully restores an acyanotic state, complications including thromboemboli are common. In a cohort of 261 patients with Fontan palliation, thromboemboli accounted for 25% of late deaths and occurred at a median age of 25 years [6]. Patients in whom thromboemboli were detected clinically and those without antiplatelet or anticoagulant therapy were at increased risk of mortality due to thromboemboli. Thrombus was primarily located within the right atrium/Fontan pathway although an occasional clot was confined to pulmonary arteries. Thromboembolic event rates appear to be similar with intracardiac lateral tunnel and extracardiac Fontans [7]. Propensity for thrombus formation has been associated with atrial arrhythmias, distended and sluggish Fontan pathways, venous stasis, intravascular prosthetic material and hepatic impairment with clotting factor abnormalities [8]. The latter include decreased levels of protein C, protein S and antithrombin III [9]. Increased platelet reactivity has also been documented [10]. Thrombosis prevention in Fontan patients
Management guidelines for adults with Fontan palliation recommend warfarin therapy in patients with any of the following criteria: atrial arrhythmias, prior thromboembolic event, documented atrial shunt or atrial thrombus [11]. However, in the absence of these factors, the role of routine antiplatelet or anticoagulation therapy remains contentious. There is little evidence for the moment to support one strategy over the other. In a recent prospective randomized trial of aspirin versus warfarin in children with Fontan palliation, no significant difference was observed between the two strategies (i.e., 7 and 6% clinical thrombosis over 2 years, respectively) [12]. However, study power was limited by slower than expected enrolment and a follow-up of only two years. In a New England Fontan registry of 210 patients followed for over 14 years, prophylaxis with either aspirin or warfarin offered significant protection against incident thromboembolic events, with no difference between the two therapies [13]. Arrhythmias in congenital heart disease
Patients with congenital heart disease may have conduction system anomalies, surgical incisions, scars, pre-existing hypoxia and/or hemodynamic sequelae that predispose to arrhythmias. The prevalence of arrhythmias increases with age such that, by adulthood, they are the leading cause of morbidity and hospital admissions [14]. It has been estimated that over 50% of adults with congenital heart disease will have suffered an atrial tachyarrhythmia before the age of 65 [15]. Moreover, sudden cardiac death of presumed arrhythmic etiology, together with heart failure, are the most common causes of mortality in patients with congenital heart disease [16]. While macroreentrant atrial circuits (i.e., intra-atrial reentrant tachycardia) are the most common arrhythmias in congenital heart disease, atrial fibrillation is increasing in 1580
prevalence in this growing and aging population [17]. In a cross-sectional analysis of 38,430 adults with congenital heart disease, atrial tachyarrhythmias were prevalent in 15% of patients [15]. Among the congenital heart disease subtypes associated with the highest prevalence of atrial tachyarrhythmias were Ebstein’s anomaly, transposition of the great arteries, univentricular hearts, atrial septal defects and tetralogy of Fallot [15]. Thrombosis prevention in patients with congenital heart disease and atrial arrhythmias
Few studies have explored the association between atrial tachyarrhythmias and thromboembolic complications in congenital heart disease [1,6,15]. In a series of 19 patients with congenital heart disease and atrial tachyarrhythmias who underwent transesophageal echocardiography, atrial thrombus was detected in 7 patients (37%; 6 right atrium; 1 left atrium) [18]. A strategy of anticoagulation with warfarin targeting internationalized normal ratio (INR) values ‡2 for at least 4 weeks prior to cardioversion, with transesophageal echocardiography reserved for high risk patients (e.g., complex congenital heart disease, mechanical valve, prior thromboemboli, systemic hypertension, heart failure or ventricular dysfunction), was associated with a low rate of cardioversion-induced systemic thromboemboli [19]. While results of clinical trials in patients with atrial fibrillation or flutter at large are often extrapolated, there is a scarcity of data regarding indications and selection of antiplatelet versus antithrombotic agents, therapeutic doses and targets, bleeding complications and efficacy outcomes specific to congenital heart disease. Limitations of current therapy
A paucity of evidence-based data is currently available to guide the timing and choice of thromboprophylactic strategies in patients with congenital heart disease. Drawbacks of warfarin therapy in young patients are well known such that achieving and maintaining therapeutic INRs can be particularly challenging in children and adolescents. For example, a study in Fontan patients found that only 30% had therapeutic INR levels (i.e., ‡2.0) [12,20]. It is, indeed, unlikely that warfarin can outperform regularly taken antiplatelet therapy if the majority of patients fail to achieve therapeutic levels. Moreover, studies in Fontan patients suggest that while prophylaxis with either antiplatelet or warfarin therapy appears to offer significant protection, the residual thromboembolic risk is considerable (e.g., 14% over 20 years) [13]. Although it remains possible that increased vigilance can improve rates of therapeutic INR levels, it may well be time to consider evaluating newer antiplatelet agents or oral anticoagulants that do not require frequent blood monitoring in patients with congenital heart disease at risk for thromboembolic events. Future perspective
Management approaches for thromboprophylaxis in patients with congenital heart disease are likely to be refined in the near Expert Rev. Cardiovasc. Ther. 11(12), (2013)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
Thrombosis in CHD
Editorial
future. The North American Alliance for Adult Research in Congenital Cardiology (AARCC) is currently conducting a multicenter observational study (i.e., the anti-coagulation therapy study in congenital heart disease [TACTIC] ) to: better define the population of patients with congenital heart disease who have atrial tachyarrhythmias or Fontan surgery; characterize prescription patterns for antiplatelet and anticoagulation therapy in this patient population; and assess the incidence of bleeding complications and thromboembolic events and explore associated factors. The hope is that such data may provide the foundation for future clinical trials.
thromboembolic events, or atrial shunts. Some form of antiplatelet or anticoagulation therapy may nevertheless be reasonable for other Fontan patients, though little evidence favors one strategy over the other. Although patients with congenital heart disease and atrial tachycarrhythmias are often prescribed antiplatelet or anticoagulation therapy, this practise is largely extrapolated from the general adult literature, with little data available to guide specific recommendations. Multicenter efforts are underway to shed light on these complex issues. Ultimately, clinical trials will be required to define optimal treatment approaches.
Conclusion
Financial & competing interests disclosure
Thromboembolic complications are an important source of morbidity and mortality in congenital heart disease. The varied pathophysiology includes disordered hemostasis, hypercoagulable states, passage of thrombus across shunts, chamber distention with sluggish flow, intracardiac thrombogenetic material, mechanical valves, endocarditis and premature atherosclerosis. Among the largest congenital heart disease subgroups at risk for thromoemboli are those with Fontan palliation and atrial tachyarrhythmias. Current guidelines for Fontan patients recommend warfarin in those with atrial arrhythmias, prior
P Khairy is supported by a Canada Research Chair in Electrophysiology and Adult Congenital Heart Disease. He has received investigator-initiated research grants from Medtronic, St. Jude Medical, Actelion, and Boehringer-Ingelheim. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
1
2
3
4
5
6
Hoffmann A, Chockalingam P, Balint OH et al. Cerebrovascular accidents in adult patients with congenital heart disease. Heart 96(15), 1223–1226 (2010). Desimone CV, Friedman PA, Noheria A et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation 128(13), 1433–1441 (2013). Khairy P, Landzberg MJ, Gatzoulis MA et al. Transvenous pacing leads and systemic thromboemboli in patients with intracardiac shunts: a multicenter study. Circulation 113(20), 2391–2397 (2006). McQuillen PS, Barkovich AJ, Hamrick SE et al. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke 38(2 Suppl.), 736–741 (2007). de Leval MR, Kilner P, Gewillig M, Bull C. Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience. J. Thorac. Cardiovasc. Surg. 96(5), 682–695 (1988). Khairy P, Fernandes SM, Mayer JE, Jr. et al. Long-term survival, modes of death, and predictors of mortality in patients with
www.expert-reviews.com
J. Am. Coll. Cardiol. 58(6), 645–651 (2011).
Fontan surgery. Circulation 117(1), 85–92 (2008).
References
13
Valente AM, Bhatt AB, Cook S et al. The CALF (Congenital Heart Disease in Adults Lower Extremity Systemic Venous Health in Fontan Patients) study. J. Am. Coll. Cardiol. 56(2), 144–150 (2010).
Potter BJ, Leong-Sit P, Fernandes SM et al. Effect of Aspirin and warfarin therapy on thromboembolic events in patients with univentricular hearts and Fontan palliation. Int. J. Cardiol. doi:10.1016/j. ijcard.2013.06.058 (2013) (Epub ahead of print).
14
Tomita H, Yamada O, Ohuchi H et al. Coagulation profile, hepatic function, and hemodynamics following Fontan-type operations. Cardiol. Young 11(1), 62–66 (2001).
Engelfriet P, Boersma E, Oechslin E et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. Eur. Heart J. 26, 2325–2333 (2005).
15
Bouchardy J, Therrien J, Pilote L et al. Atrial arrhythmias in adults with congenital heart disease. Circulation 120(17), 1679–1686 (2009).
16
Oechslin EN, Harrison DA, Connelly MS, Webb GD, Siu SC. Mode of death in adults with congenital heart disease. Am. J. Cardiol. 86(10), 1111–1116 (2000).
7
Khairy P, Poirier N. The extracardiac conduit is not the preferred Fontan approach for patients with univentricular hearts. Circulation 126(21), 2516–2525 (2012).
8
9
10
Ravn HB, Hjortdal VE, Stenbog EV et al. Increased platelet reactivity and significant changes in coagulation markers after cavopulmonary connection. Heart 85(1), 61–65 (2001).
11
Warnes CA, Williams RG, Bashore TM et al. ACC/AHA 2008 Guidelines for the management of adults with congenital heart disease: executive summary. J. Am. Coll. Cardiol. 52(23), 1890–1947 (2008).
17
Khairy P, Aboulhosn J, Gurvitz MZ et al. Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Circulation 122(9), 868–875 (2010).
12
Monagle P, Cochrane A, Roberts R et al. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children.
18
Feltes TF, Friedman RA. Transesophageal echocardiographic detection of atrial thrombi in patients with nonfibrillation atrial tachyarrhythmias and congenital heart disease. J. Am. Coll. Cardiol. 24(5), 1365–1370 (1994).
1581
Editorial
Ammash NM, Phillips SD, Hodge DO et al. Outcome of direct current cardioversion for atrial arrhythmias in adults with congenital heart disease. Int. J. Cardiol. 154(3), 270–274 (2012).
20
McCrindle BW, Manlhiot C, Cochrane A et al. Factors associated with thrombotic complications after the Fontan procedure: a secondary analysis of a multicenter, randomized trial of primary
thromboprophylaxis for 2 years after the Fontan procedure. J. Am. Coll. Cardiol. 61(3), 346–353 (2013).
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
19
Khairy
1582
Expert Rev. Cardiovasc. Ther. 11(12), (2013)
Editorial
Thrombosis in congenital heart disease Expert Rev. Cardiovasc. Ther. 11(12), 1579–1582 (2013)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
Paul Khairy Montreal Heart Institute Adult Congenital Center, Universite´ de Montre´al, Montreal, QC, Canada [email protected]
“While results of clinical trials in patients with atrial fibrillation or flutter at large are often extrapolated, there is a scarcity of data regarding indications and selection of antiplatelet versus antithrombotic agents, therapeutic doses and targets, bleeding complications and efficacy outcomes specific to congenital heart disease.” Thrombosis in congenital heart disease
Thromboemboli are a well-recognized source of morbidity and mortality in patients with congenital heart disease, with an overall prevalence estimated to be 10 to 100-fold higher than agematched controls [1]. The varied pathophysiology of thrombosis in the setting of congenital heart disease reflects diverse predisposing substrates and the heterogeneous patient population. For example, it has long been suspected that passage of thromboemboli from the right to left atrium across a patent foramen ovale, a remnant of the fetal circulation present in approximately 25% of the population, is implicated in the pathophysiology of cryptogenic stroke. Intracardiac leads for cardiac implantable devices are associated with a higher incidence of systemic thromboemboli in patients with patent foramen ovale [2] and other intracardiac shunts [3]. In addition to systemic thromboemboli via right to left shunts, patients with cyanotic heart disease may develop in situ thrombus in cerebral arteries, intracranial dural sinuses and cerebral veins. Hypercoagulable states associated with surgery and pregnancy, thrombosis secondary to intravascular lines and leads and prosthetic valves are also common in congenital heart disease. Moreover, Eisenmenger physiology, endocarditis and catheter interventions, such as balloon atrial septostomy, have been linked to stroke [1,4]. Other forms of
congenital heart disease may be associated with risk factors for premature atherosclerosis, such as a sedentary lifestyle (e.g., complex congenital heart disease) and hypertension (e.g., aortic coarctation). Among the two most prevalent subgroups of patients with congenital heart disease at risk for thromboembolic events are those with Fontan palliation and atrial tachyarrhythmias. Fontan palliation
Most patients with single ventricle physiology are managed by staged surgery in view of Fontan palliation. Fontan procedures are typically completed between 1.5 and 4 years of age and consist of directing systemic venous return to the pulmonary artery, often bypassing a right ventricle. Since first described in 1971, several modifications and adaptations have been proposed. While the classic Fontan that involved a valved conduit between the right atrium and pulmonary artery is now obsolete, the subsequent generation (the so-called modified Fontan) consisted of a direct anastomosis of the right atrium to a divided pulmonary artery. De Leval later pioneered a total cavopulmonary connection Fontan consisting of an end-toside anastomosis of the superior vena cava to the undivided right pulmonary artery and an intraatrial tunnel that uses a prosthetic patch to direct inferior vena caval flow to the pulmonary artery [5]. Another iteration of the Fontan involves an extracardiac conduit to channel
KEYWORDS: arrhythmia • congenital heart disease • Fontan • stroke • thromboemboli • thrombosis
www.expert-reviews.com
10.1586/14779072.2013.854703
2013 Informa UK Ltd
ISSN 1477-9072
1579
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
Editorial
Khairy
inferior vena caval flow to the pulmonary artery. While Fontan surgery successfully restores an acyanotic state, complications including thromboemboli are common. In a cohort of 261 patients with Fontan palliation, thromboemboli accounted for 25% of late deaths and occurred at a median age of 25 years [6]. Patients in whom thromboemboli were detected clinically and those without antiplatelet or anticoagulant therapy were at increased risk of mortality due to thromboemboli. Thrombus was primarily located within the right atrium/Fontan pathway although an occasional clot was confined to pulmonary arteries. Thromboembolic event rates appear to be similar with intracardiac lateral tunnel and extracardiac Fontans [7]. Propensity for thrombus formation has been associated with atrial arrhythmias, distended and sluggish Fontan pathways, venous stasis, intravascular prosthetic material and hepatic impairment with clotting factor abnormalities [8]. The latter include decreased levels of protein C, protein S and antithrombin III [9]. Increased platelet reactivity has also been documented [10]. Thrombosis prevention in Fontan patients
Management guidelines for adults with Fontan palliation recommend warfarin therapy in patients with any of the following criteria: atrial arrhythmias, prior thromboembolic event, documented atrial shunt or atrial thrombus [11]. However, in the absence of these factors, the role of routine antiplatelet or anticoagulation therapy remains contentious. There is little evidence for the moment to support one strategy over the other. In a recent prospective randomized trial of aspirin versus warfarin in children with Fontan palliation, no significant difference was observed between the two strategies (i.e., 7 and 6% clinical thrombosis over 2 years, respectively) [12]. However, study power was limited by slower than expected enrolment and a follow-up of only two years. In a New England Fontan registry of 210 patients followed for over 14 years, prophylaxis with either aspirin or warfarin offered significant protection against incident thromboembolic events, with no difference between the two therapies [13]. Arrhythmias in congenital heart disease
Patients with congenital heart disease may have conduction system anomalies, surgical incisions, scars, pre-existing hypoxia and/or hemodynamic sequelae that predispose to arrhythmias. The prevalence of arrhythmias increases with age such that, by adulthood, they are the leading cause of morbidity and hospital admissions [14]. It has been estimated that over 50% of adults with congenital heart disease will have suffered an atrial tachyarrhythmia before the age of 65 [15]. Moreover, sudden cardiac death of presumed arrhythmic etiology, together with heart failure, are the most common causes of mortality in patients with congenital heart disease [16]. While macroreentrant atrial circuits (i.e., intra-atrial reentrant tachycardia) are the most common arrhythmias in congenital heart disease, atrial fibrillation is increasing in 1580
prevalence in this growing and aging population [17]. In a cross-sectional analysis of 38,430 adults with congenital heart disease, atrial tachyarrhythmias were prevalent in 15% of patients [15]. Among the congenital heart disease subtypes associated with the highest prevalence of atrial tachyarrhythmias were Ebstein’s anomaly, transposition of the great arteries, univentricular hearts, atrial septal defects and tetralogy of Fallot [15]. Thrombosis prevention in patients with congenital heart disease and atrial arrhythmias
Few studies have explored the association between atrial tachyarrhythmias and thromboembolic complications in congenital heart disease [1,6,15]. In a series of 19 patients with congenital heart disease and atrial tachyarrhythmias who underwent transesophageal echocardiography, atrial thrombus was detected in 7 patients (37%; 6 right atrium; 1 left atrium) [18]. A strategy of anticoagulation with warfarin targeting internationalized normal ratio (INR) values ‡2 for at least 4 weeks prior to cardioversion, with transesophageal echocardiography reserved for high risk patients (e.g., complex congenital heart disease, mechanical valve, prior thromboemboli, systemic hypertension, heart failure or ventricular dysfunction), was associated with a low rate of cardioversion-induced systemic thromboemboli [19]. While results of clinical trials in patients with atrial fibrillation or flutter at large are often extrapolated, there is a scarcity of data regarding indications and selection of antiplatelet versus antithrombotic agents, therapeutic doses and targets, bleeding complications and efficacy outcomes specific to congenital heart disease. Limitations of current therapy
A paucity of evidence-based data is currently available to guide the timing and choice of thromboprophylactic strategies in patients with congenital heart disease. Drawbacks of warfarin therapy in young patients are well known such that achieving and maintaining therapeutic INRs can be particularly challenging in children and adolescents. For example, a study in Fontan patients found that only 30% had therapeutic INR levels (i.e., ‡2.0) [12,20]. It is, indeed, unlikely that warfarin can outperform regularly taken antiplatelet therapy if the majority of patients fail to achieve therapeutic levels. Moreover, studies in Fontan patients suggest that while prophylaxis with either antiplatelet or warfarin therapy appears to offer significant protection, the residual thromboembolic risk is considerable (e.g., 14% over 20 years) [13]. Although it remains possible that increased vigilance can improve rates of therapeutic INR levels, it may well be time to consider evaluating newer antiplatelet agents or oral anticoagulants that do not require frequent blood monitoring in patients with congenital heart disease at risk for thromboembolic events. Future perspective
Management approaches for thromboprophylaxis in patients with congenital heart disease are likely to be refined in the near Expert Rev. Cardiovasc. Ther. 11(12), (2013)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
Thrombosis in CHD
Editorial
future. The North American Alliance for Adult Research in Congenital Cardiology (AARCC) is currently conducting a multicenter observational study (i.e., the anti-coagulation therapy study in congenital heart disease [TACTIC] ) to: better define the population of patients with congenital heart disease who have atrial tachyarrhythmias or Fontan surgery; characterize prescription patterns for antiplatelet and anticoagulation therapy in this patient population; and assess the incidence of bleeding complications and thromboembolic events and explore associated factors. The hope is that such data may provide the foundation for future clinical trials.
thromboembolic events, or atrial shunts. Some form of antiplatelet or anticoagulation therapy may nevertheless be reasonable for other Fontan patients, though little evidence favors one strategy over the other. Although patients with congenital heart disease and atrial tachycarrhythmias are often prescribed antiplatelet or anticoagulation therapy, this practise is largely extrapolated from the general adult literature, with little data available to guide specific recommendations. Multicenter efforts are underway to shed light on these complex issues. Ultimately, clinical trials will be required to define optimal treatment approaches.
Conclusion
Financial & competing interests disclosure
Thromboembolic complications are an important source of morbidity and mortality in congenital heart disease. The varied pathophysiology includes disordered hemostasis, hypercoagulable states, passage of thrombus across shunts, chamber distention with sluggish flow, intracardiac thrombogenetic material, mechanical valves, endocarditis and premature atherosclerosis. Among the largest congenital heart disease subgroups at risk for thromoemboli are those with Fontan palliation and atrial tachyarrhythmias. Current guidelines for Fontan patients recommend warfarin in those with atrial arrhythmias, prior
P Khairy is supported by a Canada Research Chair in Electrophysiology and Adult Congenital Heart Disease. He has received investigator-initiated research grants from Medtronic, St. Jude Medical, Actelion, and Boehringer-Ingelheim. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
1
2
3
4
5
6
Hoffmann A, Chockalingam P, Balint OH et al. Cerebrovascular accidents in adult patients with congenital heart disease. Heart 96(15), 1223–1226 (2010). Desimone CV, Friedman PA, Noheria A et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation 128(13), 1433–1441 (2013). Khairy P, Landzberg MJ, Gatzoulis MA et al. Transvenous pacing leads and systemic thromboemboli in patients with intracardiac shunts: a multicenter study. Circulation 113(20), 2391–2397 (2006). McQuillen PS, Barkovich AJ, Hamrick SE et al. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke 38(2 Suppl.), 736–741 (2007). de Leval MR, Kilner P, Gewillig M, Bull C. Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience. J. Thorac. Cardiovasc. Surg. 96(5), 682–695 (1988). Khairy P, Fernandes SM, Mayer JE, Jr. et al. Long-term survival, modes of death, and predictors of mortality in patients with
www.expert-reviews.com
J. Am. Coll. Cardiol. 58(6), 645–651 (2011).
Fontan surgery. Circulation 117(1), 85–92 (2008).
References
13
Valente AM, Bhatt AB, Cook S et al. The CALF (Congenital Heart Disease in Adults Lower Extremity Systemic Venous Health in Fontan Patients) study. J. Am. Coll. Cardiol. 56(2), 144–150 (2010).
Potter BJ, Leong-Sit P, Fernandes SM et al. Effect of Aspirin and warfarin therapy on thromboembolic events in patients with univentricular hearts and Fontan palliation. Int. J. Cardiol. doi:10.1016/j. ijcard.2013.06.058 (2013) (Epub ahead of print).
14
Tomita H, Yamada O, Ohuchi H et al. Coagulation profile, hepatic function, and hemodynamics following Fontan-type operations. Cardiol. Young 11(1), 62–66 (2001).
Engelfriet P, Boersma E, Oechslin E et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. Eur. Heart J. 26, 2325–2333 (2005).
15
Bouchardy J, Therrien J, Pilote L et al. Atrial arrhythmias in adults with congenital heart disease. Circulation 120(17), 1679–1686 (2009).
16
Oechslin EN, Harrison DA, Connelly MS, Webb GD, Siu SC. Mode of death in adults with congenital heart disease. Am. J. Cardiol. 86(10), 1111–1116 (2000).
7
Khairy P, Poirier N. The extracardiac conduit is not the preferred Fontan approach for patients with univentricular hearts. Circulation 126(21), 2516–2525 (2012).
8
9
10
Ravn HB, Hjortdal VE, Stenbog EV et al. Increased platelet reactivity and significant changes in coagulation markers after cavopulmonary connection. Heart 85(1), 61–65 (2001).
11
Warnes CA, Williams RG, Bashore TM et al. ACC/AHA 2008 Guidelines for the management of adults with congenital heart disease: executive summary. J. Am. Coll. Cardiol. 52(23), 1890–1947 (2008).
17
Khairy P, Aboulhosn J, Gurvitz MZ et al. Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Circulation 122(9), 868–875 (2010).
12
Monagle P, Cochrane A, Roberts R et al. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children.
18
Feltes TF, Friedman RA. Transesophageal echocardiographic detection of atrial thrombi in patients with nonfibrillation atrial tachyarrhythmias and congenital heart disease. J. Am. Coll. Cardiol. 24(5), 1365–1370 (1994).
1581
Editorial
Ammash NM, Phillips SD, Hodge DO et al. Outcome of direct current cardioversion for atrial arrhythmias in adults with congenital heart disease. Int. J. Cardiol. 154(3), 270–274 (2012).
20
McCrindle BW, Manlhiot C, Cochrane A et al. Factors associated with thrombotic complications after the Fontan procedure: a secondary analysis of a multicenter, randomized trial of primary
thromboprophylaxis for 2 years after the Fontan procedure. J. Am. Coll. Cardiol. 61(3), 346–353 (2013).
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Case Western Reserve University on 10/31/14 For personal use only.
19
Khairy
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Expert Rev. Cardiovasc. Ther. 11(12), (2013)
