Budesonide seems to have fewer systemic effects than other oral steroids; how- ever, close monitoring for signs of hypercortisolism Octreotide may be con- sidered; it is a therapy with favorable but very limited anecdotal experience reported, with further research A combination of these therapies may be applied in an affected patient, as such strat- egies collectively appear to have produced improved outcome compared with historic controls.S4.4.2-31 Fontan surgery has been associated with prolonga- tion of atrial refractory periods, extensive atrial scar- ring, and intra-atrial conduction delay.S4.4.2-32 S4.4.2-38 Si- nus node dysfunction occurs in up to 45% of adults during long-term follow-up after Fontan surgery and has been associated with a reduction in preload to the single ventricle, increased pulmonary venous pres- sure, reduced cardiac output, plastic bronchitis, and Transvenous atrial pacing may be feasible in most adults with atrio- pulmonary Fontan connections and in some with intra- cardiac lateral tunnels,S4.4.2-44 although the potential for thrombotic complications must be addressed. Ventric- ular pacing may be performed via the coronary sinus in selected patients, but most require an epicardial Management of atrial arrhyth- mias is discussed in the associated recommendations. See Section 3.3 for recommendations on who should perform surgeries, cardiac catheterization and other procedures in these patients; Section 3.4 for rec- ommendations on diagnostic evaluation; and Table 32 for routine testing and follow-up intervals. Recommendation-Specific Supportive Text 1. Atrial tachyarrhythmias occur in up to 60% of adults with Fontan palliation and are associated These arrhythmias may be difficult to manage, are usually poorly tolerated, and cause serious hemodynamic compromise often with dire consequences.S4.4.2-1 Therefore, they should be addressed promptly, including urgent consultation with ACHD provid- ers who can help guide immediate management strategies, even if remotely. Consideration for anti- thrombotic therapy in Fontan patients should take into account the high prevalence of thrombus for- mation and potentially catastrophic impact of pul- monary or systemic thromboembolus. Standard Recommendations for Fontan Palliation of Single Ventricle Physiology (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES decision-making strategies about rhythm versus rate control or thromboembolic prophylaxis de- rived from and recommended for patients with acquired heart disease and AF do not apply to patients with Fontan physiology, for whom rhythm control and anticoagulation are of greater impor- tance than would be concluded from application of the standard algorithms. Sinus node dysfunction may predispose Fontan patients to atrial tachyarrhythmias, the most common being macro-reentrant circuits or intra-atrial reentrant tachycardia.S4.4.2-13,S4.4.2-47 Nearly 90% of Fontan patients who die from HF have coexisting atrial tachyarrhythmias.S4.4.2-48 Fontan patients are at increased risk of complica- tions from antiarrhythmic therapy, such as tors- ades de pointes with dofetilideS4.4.2-49 and amio- Such agents should be used cautiously and in consultation with ACHD cardiologists and electrophysiology specialists with expertise in ACHD. 2. Serial imaging can be valuable for assessing many of the long-term sequelae of Fontan palliation such as thrombosis, right-to-left shunts (eg, fen- estration, intrapulmonary AV malformation), ob- structive lesions, systemic AV valve dysfunction, diastolic or systolic ventricular function, collat- eral burden, and branch PA obstruction. Imaging can be challenging and requires informed un- derstanding about the patient's particular situa- tion. Although CCT is possible in patients with Fontan physiology, it is challenging to ensure contrast dispersal through the pulmonary vas- culature because of streaming of venous return to the PA from multiple separate sources (eg, superior vena cava, inferior vena cava right atrium 3. Hemodynamic assessment, particularly of the pul- monary circulation, is crucial to making informed decisions about the type and timing of surgical intervention. 4. Hemodynamic problems may first manifest through arrhythmia. Thus, first presentation of arrhythmia should warrant thorough review of the patient s Fontan circulation and ventricular function. 5. Aerobic exercise may help maintain respiratory mechanics, which can improve transpulmonary flow in the Fontan circulation. Stroke volume dur- ing exercise and exercise capacity are directly re- lated to skeletal muscle function. Consequently, strength training may improve exercise capacity in patients with Fontan palliation. 6. There is increasing recognition of hepatic vul- nerability after Fontan palliation, including but uncertainty about which patients are at highest risk, or how to address problems when identified. Routine assessment of liver function and structure may help inform broader decisions such as timing and risk of sur- gery or transplantation, as well as provide insights into the emerging natural history of this unique condition. Consultation with a hepatologist may be of value in interpreting and following the liver abnormalities encountered in patients with Fontan physiology. 7. Recognizing the multiorgan vulnerability of the Fontan circulation, annual routine blood tests Table 32. Fontan Palliation: Routine Follow-Up and Testing Intervals Frequency of Routine Follow-Up and Testing Physiological Stage A* (mo) Physiologic al Stage B* (mo) Physiological Stage C* (mo) Physiological Stage D* (mo) Pulse oximetry 12 12 Each visit Each visit *See Tables 3 and 4 for details on the ACHD AP classification system. Routine TTE may be unnecessary in a year when CMR imaging is performed unless clinical indications warrant otherwise. CMR may be indicated for assessment of the long-term sequelae of Fontan palliation: thrombosis, right-to-left shunts (eg, fenestration. intrapulmonary atrioventricular malformation), obstructive lesion, systemic atrioventricular valve dysfunction, ventricular size and function, collateral burden, and branch pulmonary artery obstruction. Baseline study is recommended with periodic follow- up CMR, with frequency of repeat imaging determined by anatomic and physiological findings. CCT may be used if CMR is not feasible and to evaluate cross-sectional imaging status-post stent therapy. CCT with contrast injection in Fontan patients can be misleading; therefore, it should be done only when clinically indicated and when it can be appropriately protocoled and interpreted. If CCT is used instead of CMR imaging, the frequency should be weighed against radiation exposure. 6-minute walk test or CPET, depending on clinical indication. ACHD indicates adult congenital heart disease; CCT, cardiac computed tomography; CMR, cardiovascular magnetic resonance imaging; CPET, cardiopulmonary exercise test; ECG, electrocardiogram; and TTE, transthoracic echocardiogram. CLINICAL STATEMENTS AND GUIDELINES may have a role in identifying and addressing problems early. 8. Because of both the anatomic and physiological complexities of these patients, and the potential for concurrent intervention, hemodynamic and interventional cardiac catheterization of the adult with single ventricle/Fontan palliation should be performed only by persons with expertise in CHD in coordination with an ACHD cardiologist. Recognizing that it is difficult to accurately assess Fontan hemodynamics by clinical examination or noninvasive imaging, cardiac catheterization may be needed in these scenarios and others: a. Interval hemodynamic assessment, as filling pressures, mean PA pressure, and pulmonary vascular resistance may change over timeS4.4.2-8 b. Creation or closure of a fenestration or veno- veno collaterals, although with uncertain ben- efit of either interventionS4.4.2-54 S4.4.2-56 c. Treatment of baffle obstruction, even in the setting of low or no pressure gradientS4.4.2-57 d. Assessment of protein-losing enteropathy or ascites, because elevated Fontan pressure cor- relates with such complications, and lowering pressures may offer the potential for clinical e. Facilitation of transvenous liver biopsy for monitoring liver function including as part of a pretransplantation assessment f. Preoperative assessment before Fontan 9. Protein-losing enteropathy and plastic bronchitis contribute substantially to perioperative mortality, yet transplantation may be curative.S4.4.2-9,S4.4.2-11 Medical therapy options are often ineffective. Therefore, consideration of transplantation early in the course of PLE may be warranted. Evaluation of additional organs is necessary, particularly the liver, as these patients are susceptible to cirrhosis as a consequence of the Fontan circulation. Although symptoms may improve, there are no published data regarding impact on survival for transplanted Fontan patients with PLE compared with those who do not undergo transplantation. 10. Although catheterization plays an important role in management of single ventricle/Fontan patients, it is often driven by symptoms. The role of routine hemodynamic assessment is less certain. 11. Fontan circulation imparts risk of thrombosis, and anticoagulation with vitamin K antagonists should be offered as preventive therapy in clin- ical situations including prior arrhythmia.S4.4.2-60 Patients may also benefit from anticoagulation if they have significant residual intracardiac right- to-left shunt or veno-veno collaterals. 12. Catheter ablation has been associated with improved clinical status despite the frequent co- existence of multiple arrhythmia substrates.S4.4.2-61 Given the progressive nature of the atrial myop- athy, successful ablation is less frequent than in acquired heart disease or other congenital heart diseases, and recurrence is common. The devel- opment of new arrhythmias over time remains problematic, but multiple ablation procedures may be justified in selected patients.S4.4.2-13,S4.4.2-14 13. Conversion to a total cavopulmonary connec- tion Fontan combined with a modified right atrial Maze procedure may be considered in patients with symptomatic refractory recurrent intra-atrial In the pres- ence of documented AF, a left atrial Cox Maze procedure may also be indicated.S4.4.2-16,S4.4.2-62 Some patients may not be appropriate surgical candidates for reasons of elevated PA or Fontan pressures, elevated ventricular end-diastolic pres- sures, or renal or hepatic dysfunction, and the de- cision to perform Fontan revision surgery is rarely straightforward. 14. Pulmonary vasoactive medications, specifically endothelin receptor antagonists and PDE-5 inhibitors, are of increasing interest as a means of reducing pulmonary vascular resistance and improving cardiac output. In limited studies, use of PDE-5 inhibitors appears favorable for Fontan patients with improvement noted in pulmonary blood flow and exercise capacity.S4.4.2-21,S4.4.2-63 Use of endothelin antagonists has been investigated in a randomized trial.S4.4.2-19 After 14 weeks of ran- domization in 69 subjects successfully completing the study, there was a modest but significant in- crease in peak oxygen consumption and exercise duration in those taking bosentan compared with those on placebo. 15. Although anticoagulation is prudent in those with prior arrhythmia or known thromboem- bolic events, routine use of anticoagulation with vitamin K antagonist cannot as yet be strongly recommended. An RCT in Fontan children/ado- lescents did not show benefit,S4.4.2-64 although adults later after Fontan may be more at risk. However, a secondary analysis of that RCT as an found the risk of throm- boembolism was lower in those patients on war- farin who consistently achieved minimum target international normalized ratio levels, as well as in those on acetylsalicylic acid compared with patients who often failed to meet target interna- tional normalized ratio level. Rates of thrombosis were considerably higher in patients on warfarin who did not consistently achieve target inter- national normalized ratio. A study of modes of CLINICAL STATEMENTS AND GUIDELINES death in atriopulmonary Fontan patients dem- onstrated lower rates of death in patients on some antiplatelet agent or anticoagulation compared with those on none.S4.4.2-1 Direct oral anticoagulants are unstudied and thus cannot be recommended at the present time. There are con- cerns about liver function vulnerability in Fontan patients, which theoretically may increase the risk of complications with some of those agents. 16. There are occasions where surgery or catheter intervention may be alternatives to transplanta- tion for a failing Fontan after weighing risks and benefits of the intended procedure (ie, alle- viation of atrioventricular valve regurgitation, sys- temic or pulmonary venous pathway obstruction). Reoperation for atrioventricular valve regurgita- tion may be high-risk, particularly when systemic ventricular function is impaired. Although valve repair is preferred and operative risk is usually lower, it is not always possible. Risk of valve re- placement in this setting is high. 4.4.3. Hypoplastic Left Heart Syndrome/Norwood Repair The Norwood repair is the first of 3 steps in palliation for hypoplastic left heart syndrome and consists of a- trial septectomy, transection, and ligation of the distal main PA with construction of a systemic-to-PA shunt, and anastomosis of the proximal stump of the main PA to the hypoplastic ascending aorta with augmentation of the entire aortic arch from the sinotubular junction to beyond the ductus arteriosus. Hypoplastic left heart syndrome is fatal unless surgical palliation is performed in the neonatal period. Subsequent surgeries include a bidirectional cavopulmonary anastomosis (often per- formed around 6 months of age), followed finally by a Fontan procedure (often at approximately 2 to 4 years of age). Sequelae of hypoplastic left heart syndrome are largely those of the Fontan palliation, but additional concerns related to the underlying anatomy and the Norwood repair is important in patients with hypoplas- tic left heart syndrome. These include aortic obstruction related to anastomosis of the PA and aorta, and neo- aortic dilation. Additionally, native anatomy wherein coronary arteries arise from a small aortic root make coronary ischemia a greater concern than in other un- derlying disorders managed with Fontan repair. The fre- quency and spectrum of long-term sequelae specific to the Norwood repair are not yet known. 4.4.4. Truncus Arteriosus Truncus arteriosus in the adult has almost invariably been repaired in childhood, and in the rare circum- stances when an adult has unrepaired truncus arte- riosus, Eisenmenger physiology is typical. Pulmonary hypertension may be present in repaired patients. The types of operative repairs may involve VSD clo- sure, right ventricle to-PA conduit placement, recon- struction of the pulmonary arteries, and replacement of the truncal (neoaortic) valve. Unifocalization of the pulmonary arteries may be necessary in very complex cases. The aorta may be dilated. Recommendations regarding assessment and management of truncus arteriosus can generally be inferred in the recommen- dations for the specific components, including right ventricle to-PA conduit, VSD, aortic valve disease, and aortopathies. 4.4.5. Double Outlet Right Ventricle Double outlet right ventricle is an anatomic descrip- tor that includes abnormalities similar to TOF in some patients (when the aorta is closely related to the VSD) and similar to d-TGA with a VSD in others (when the PA is more closely related to the VSD than the aorta). Repairs are predicated on the underlying anatomy and may involve VSD closure with relief of PS, right ventricle to-PA conduit, or Rastelli-type repair. In se- vere cases, single-ventricle physiology may be present. Consequently, recommendations for the management of a patient with double outlet right ventricle can gen- erally be inferred in the recommendations for the le- sion with the most similar anatomy and physiology (eg, TOF can reasonably be based on the recommen- dations in Section 4.4.1, recognizing that a patient with double outlet right ventricle is more likely to have residual LVOT obstruction). 4.4.6. Severe PAH and Eisenmenger Syndrome 4.4.6.1. Severe PAH Recommendations for Severe PAH Referenced studies that support recommendations are summarized in Online Data Supplement 49. COR LOE Recommendations Diagnostic I B-NR Patients with ACHD with pulmonary vascular resistance 2.5 Wood units or greater ) should be assessed collaboratively by an ACHD cardiologist and an expert in pulmonary hypertension to develop a management plan.S4.4.6.1-1 S4.4.6.1-17 I B-NR Adults with septal or great artery shunts should undergo periodic screening for pulmonary hypertension with I B-NR Cardiac catheterization to assess pulmonary vascular hemodynamics is recommended for adults with septal or great artery shunts and clinical symptoms, signs, or echocardiographic findings suggestive of I B-NR In adults with septal or great artery shunts, cardiac catheterization with hemodynamics (performed before or at time of closure) is beneficial to assess suitability for CLINICAL STATEMENTS AND GUIDELINES Diagnostic (Continued) I C-EO BNP, chest x-ray, 6-minute walk test, and cardiac catheterization are useful for initial and follow-up evaluation of patients with ACHD with PAH. Synopsis Pulmonary hypertension is defined as elevation of mean pulmonary arterial pressure to 25 mm Hg at rest and does not imply a specific underlying pathophysiology. Pulmonary hypertension is further classified on the ba- sis of the presumed mechanism (including elevation of pulmonary venous pressure [denoted as postcapillary pulmonary hypertension ], parenchymal or restrictive lung disease, rheumatologic disease, portal hyperten- sion, toxin exposure, and thromboembolism). It is also classified by developmental or acquired anatomic ab- normalities of decreased pulmonary arterial capacitance, impedance, or stenosis throughout the pulmonary arte- rial vascular bed. PAH as initially described required pul- monary venous pressure 15 mm Hg with concomitant elevation of pulmonary vascular resistance. Although left-to-right shunting was the initial research model of triggered PAH, pulmonary hypertension in patients with ACHD can be caused by, or associated with, any of the factors described above. Effective therapies may be spe- cific to the primary mechanism of pulmonary hyperten- sion in a given patient, so patients with CHD should have thorough investigation for all potential contributing eti- ologies to pulmonary hypertension that may require spe- cific therapy if best clinical outcomes are to be achieved. Adverse effects of pulmonary hypertension therapies in patients with ACHD with pulmonary hypertension may differ from those noted in other patients, because of concomitant multiorgan and vascular effects from long- standing congenital heart and vascular disease. Shunt-related PAH in patients with ACHD can de- velop in the pre- or perioperative period but also may develop years to decades after closure of defects. Mechanisms for development of PAH may include ge- netic factors and environmental exposures. Severity of PAH may range from incidentally noted mild pressure and resistance elevation to profound systemic or supra- systemic levels of PA pressure and pulmonary vascular resistance. If an anatomic defect that allows shunting is present, shunt reversal and cyanosis may develop as pulmonary resistance rises above systemic resistance (ie, Eisenmenger syndrome). See Section 3.3 for recommendations on who should perform surgeries, cardiac catheterization, and other procedures in these patients; Section 3.4 for rec- ommendations on diagnostic evaluation; and Table 33 for routine testing and follow-up intervals. Recommendation-Specific Supportive Text 1. Patients with ACHD with pulmonary hyperten- sion, particularly PAH, have a poorer prognosis than do patients with ACHD with similar histo- ries and anatomic abnormalities who do not have pulmonary hypertension. The fields of ACHD and pulmonary vascular disease care have increasingly disparate but complementary bodies of know- ledge, and both are necessary to achieve op- timal outcomes for patients with PAH. Clinicians cross-trained in both subspecialties or partnering experts from each subspecialty appear necessary to fully counsel patients with ACHD with PAH re- garding: diagnostic evaluation, prognosis, lifestyle choices, suitability for operative or catheter-based repair of existing shunts or vascular obstructions contributing to PAH, nature and effectiveness of additional medical therapies, mechanical circula- tory and pulmonary vascular support, and goals of care. 2. PAH may develop years after shunt closure in patients with ACHD. Predictors for the develop- ment or presence of PAH include: a. Anatomic defects: complete AVSD, sinus ve- nosus defect, large nonrestrictive defect (ASD >2 cm, VSD >1 cm, PDA >0.6 cm), and concomitant ACHD AP classification II or III abnormalities. b. Preintervention Qp:Qs 3 and/or PASP >40 mm Hg. c. Presence of associated syndrome (eg, Down syndrome). Recommendations for Severe PAH (Continued) COR LOE Recommendations Table 33. Pulmonary Hypertension and Eisenmenger Syndrome: Routine Follow-Up and Testing Intervals Frequency of Routine Follow-Up and Testing Physiological Stage C* (mo) Physiological Stage D* (mo) Outpatient ACHD cardiologist 6 12 3 6 Pulse oximetry Each visit Each visit CMR As needed As needed Cardiac catheterization As needed As needed *See Tables 3 and 4 for details on the ACHD AP classification system. Routine TTE may be unnecessary in a year when CMR imaging is performed unless clinical indications warrant otherwise. CMR may be indicated for assessment of right ventricular function and CHD anatomy not clarified with TTE. Baseline study is recommended with periodic follow-up CMR, with frequency of repeat imaging determined by anatomic and physiological findings. 6-minute walk test or CPET, depending on clinical indication. Cardiac catheterization should be performed at baseline and as needed. ACHD indicates adult congenital heart disease; CMR, cardiovascular magnetic resonance; CPET, cardiopulmonary exercise test; ECG, electrocardiogram; and TTE, transthoracic echocardiogram. CLINICAL STATEMENTS AND GUIDELINES d. Older age at repair. e. Female sex. f. Otherwise unexplained symptoms potentially attributable to PAH (decreased exercise ca- pacity, syncope, chest pain, hemoptysis). g. Findings on clinical examination: systemic ar- terial desaturation, elevated systemic venous pressures, other evidence of fluid retention, loud P2, new TR or PR, new arrhythmia, decreased exercise capacity, electrocardi- ographic findings consistent with subpul- monary ventricular hypertrophy or dilation. Echocardiography may demonstrate subpul- monic ventricular dysfunction and/or enlarge- ment and estimate central venous and PA pressures. However, echocardiography alone is insufficient to accurately determine PA pressure or pulmonary vascular resistance, so echocardiography is best used in conjunction with data obtained at cardiac catheterization when making decisions about instituting or changing therapy for PAH.S4.4.6.1-19 S4.4.6.1-21 3. Cardiac catheterization remains the standard for accurate diagnosis of pulmonary hypertension syndromes and for selection of optimal thera- pies for patients with ACHD with pulmonary hypertension. 4. Mechanical interventions targeting relief of ana- tomic contributors to PAH (eg, closure of septal or great arterial defects to eliminate shunting) may be considered as part of short-term plans of care for patients with ACHD with PAH. However, even modest residual levels of PAH substantially determine intermediate and longer-term out- comes. Patients should be followed for pulmo- nary hypertension. 5. Although history, noninvasive testing, and labo- ratory analysis (biochemistry and hematology) are all part of the workup of pulmonary hyperten- sion associated with CHD, cardiac catheterization with careful hemodynamic measurements, with or without provocative maneuvers and/or angiog- raphy, remains fundamental to accurate diagnosis and design of therapeutic plans. 4.4.6.2. Eisenmenger Syndrome Recommendations for Eisenmenger Syndrome Referenced studies that support recommendations are summarized in Online Data Supplement 50. COR LOE Recommendations Diagnostic I C-EO When evaluating adults with presumed Eisenmenger syndrome, clinicians should confirm diagnostic imaging and cardiac catheterization data accuracy and exclude other potential contributors to right-to-left shunting or pulmonary hypertension. Therapeutic I A Bosentan is beneficial in symptomatic adults with Eisenmenger syndrome with ASD or IIa B-R In symptomatic adults with Eisenmenger syndrome, bosentan and PDE-5 inhibitors are reasonable in combination if symptomatic improvement does not occur with either IIa C-EO Bosentan is a reasonable therapy to treat symptomatic adults with Eisenmenger syndrome with 1 of the following: shunts other than ASD/VSD (eg, PDA, aortopulmonary window) (Level of Evidence C-EO), or complex congenital or Down (Level of Evidence B-NR). B-NR IIa B-NR It is reasonable to use PDE-5 inhibitors (eg, sildenafil, tadalafil) to treat symptomatic adults with Eisenmenger syndrome with ASD, VSD, or great artery Synopsis Historically Eisenmenger syndrome has been under- stood as the most advanced form of PAH associated with congenital intracardiac and great arterial shunting. The natural course and outcomes of PAH in patients with ACHD with Eisenmenger syndrome, as contrasted to other adults with PAH, remain incompletely defined. However, it is believed that better survival and func- tional ability of untreated adults with Eisenmenger syn- drome might be explained by sharing of loading condi- tions between right- and left-sided cardiac chambers, as well as multiorgan system adaptations that develop over time. The fundamental cause of Eisenmenger syndrome is elevated pulmonary vascular resistance driving right- to-left intracardiac or great arterial shunting leading to systemic arterial desaturation. The risk of development of Eisenmenger syndrome is influenced by concomitant congenital syndromes, anatomic location of congenital defects, size of anatomic defects, genetic factors, and environmental exposures. Pathophysiological mechanisms contributing to de- velopment of Eisenmenger syndrome are not fully un- derstood. Suggested triggers and pathways include blood flow-induced shear and circumferential stress, vasoconstriction, and vascular cell proliferation associ- ated with fibrosis and thrombosis. Cyanosis, erythrocytosis, abnormalities of loading conditions, and abnormalities of systemic and pulmo- nary perfusion all contribute to functional incapacity and potential for multiorgan system dysfunction and other sequelae, including stroke, brain abscess, osteo- Recommendations for Eisenmenger Syndrome (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES arthropathy, iron deficiency, reduced glomerular clear- ance and susceptibility to acute renal insufficiency, ne- phrosis, pulmonary arterial thrombosis and dissection, hemoptysis, pulmonary parenchymal infections, dias- tolic and systolic cardiac dysfunction, arrhythmia, HF, and SCD. Palliative therapies that may be helpful include sup- plemental oxygen if systemic arterial oxygen saturation is empirically noted to rise in response, systemic antico- agulation, and avoidance of circumstances recognized to contribute to risk (eg, high altitude, pregnancy, ex- posure to high heat or humidity leading to vasodilation, nephrotoxin exposure, extreme exertion, large shifts in intravascular volume). However, supportive data for these strategies are limited or nonexistent. Systemic an- ticoagulation has the potential for adverse as well as possible helpful effects. Mechanical circulatory and pulmonary support, lung transplantation with concomitant repair of anatomic cardiovascular defects, and heart lung transplantation have all been applied in patients with ACHD with Eisen- menger syndrome with deteriorating functional ability. Indications for such therapies for adults with Eisen- menger syndrome are not standardized; comparative outcomes have not been tested, and to date successes have been limited. However, pharmacological treat- ment of PAH is helpful in the management of certain patients with Eisenmenger syndrome. See Section 3.3 for recommendations on who should perform surgeries, cardiac catheterization, and other procedures in these patients; Section 3.4 for rec- ommendations on diagnostic evaluation; and Table 33 for routine testing and follow-up intervals. Recommendation-Specific Supportive Text 1. Right-to-left shunting through septal defects or connections between the great arteries associ- ated with subpulmonary ventricular hypertension may be diagnosed as Eisenmenger syndrome. PAH medications may be beneficial for patients with Eisenmenger syndrome; however, other conditions may cause right-to-left shunting for reasons other than shunt-related PAH and thus may require different treatment options. These other conditions include: a) severe pulmonary hy- pertension of other cause (eg, thromboembolic disease, rheumatic disease), b) subpulmonary chamber outflow obstruction, c) abnormalities of subpulmonary chamber compliance, and d) vas- cular streaming. Accurate diagnosis is necessary to guide therapy. For example, PAH therapies will not be beneficial if the source of right-to- left shunting is RVOT obstruction; rather, allevi- ation of the RVOT obstruction is the necessary treatment. Accurate diagnosis of Eisenmenger syndrome and exclusion of other potential con- tributors to right-to-left shunting or pulmonary hypertension by means of advanced imaging and cardiac catheterization are crucial prerequisites to optimize therapy for adults with Eisenmenger syndrome. 2. In adults with Eisenmenger syndrome associated with ASD or VSD in World Health Organization functional class III or IV, RCTs demonstrate improved 6-minute walk distance, hemody- namics, and subjective functional ability after 4 months of oral bosentan.S4.4.6.2-17 Longer-term benefit has been demonstrated through open- label extension of this initial RCTS4.4.6.2-1 and in single-center registry cohorts.S4.4.6.2-1,S4.4.6.2-17 There may be a class effect for endothelin receptor antagonists, but others have not been studied in this population. 3. A randomized crossover trial of combination PAH therapy (PDE-5 inhibitor therapy and endothelin receptor antagonist therapy) enrolled adults with Eisenmenger syndrome or with idiopathic PAH and demonstrated improvement in systemic ar- terial saturation but not in functional ability or Use of combination PAH therapy for adults with Eisenmenger syndrome was further supported by a single-center co- hort series suggesting improvement in 6-minute walk testing and hemodynamics in adults with Eisenmenger syndrome using combined PDE-5 in- hibitory therapy and endothelin receptor antago- 4. Open-label single-center registries and cohort studies of adults with Eisenmenger syndrome, attributable to shunts other than ASD/VSD or with complex congenital heart lesions, suggest benefit in functional capacity or hemodynamics after months of endothelin receptor antagonist Patients with ACHD and Down syndrome have greater likelihood to de- velop pulmonary hypertension, and they have unique comorbidities that influence the nature of their pulmonary hypertension, the metrics used in follow-up, and the potential for benefit from as well as adverse response to therapy. Open-label single-center registries and cohorts of adults with Down syndrome and Eisenmenger syndrome suggest benefit in subjective and/or objective functional capacity after months of endothelin re- ceptor antagonist therapy, generally as contrasted to performance before institution of endothe- lin receptor antagonist therapy.S4.4.6.2-8 S4.4.6.2-10 Accurate diagnosis of PAH and Eisenmenger syn- drome remains essential before initiating such therapy. CLINICAL STATEMENTS AND GUIDELINES regarding PDE-5 inhibitor therapy for adults with Eisenmenger syndrome have limita- tions, but are supported by multiple open-label prospective studies and information from a large single-center retrospective registry.S4.4.6.2-1,S4.4.6.2-11 These studies suggest benefit in functional capacity and hemodynamics after use of either sildenafil or tadalafil at varying doses and for varying periods of follow-up. Benefit was ei- ther in comparison to subjects performance before institution of therapy or to other adults with similar Eisenmenger syndrome anatomy and physiology who were not prescribed PDE-5 inhibitors. 4.4.7. Coronary Anomalies Coronary abnormalities are among the most com- mon congenital cardiovascular anomalies, surpassing in prevalence nearly all others combined. Coronary anomalies include anomalous aortic origin of a coro- nary artery (AAOCA), coronary fistula, and myocardial bridge. Many congenital coronary abnormalities have a benign outcome. In contrast, natural history studies of anomalous coronary artery from the PA (particularly anomalous left coronary artery from the PA) suggest poor outcome in untreated patients; similar natural history studies are lacking regarding untreated patients with AAOCA, but other evidence raises concern. See Table 34 and Figure 5 for a diagnostic and treatment algorithm for AAOCA. Assessment of the risk of SCD in patients with AAOCA and of the role of AAOCA in causing ische- mia or symptoms is difficult because available data do not adequately capture the clinical spectrum of these anomalies. Autopsy series are available that help de- scribe the anomalies found in patients who suffered SCD contrasted to other causes of death.S4.4.7-1 S4.4.7-5 There are surgical case series that describe findings before operation, operative anatomy and postopera- There are imaging studies describing the anatomy and potential pathophysio- logical abnormalities associated with AAOCA.S4.4.7-6, There are surgical series describing im- provement in symptoms after operation.S4.4.7-6 S4.4.7-8 There are surveys and registries that describe the heterogeneous management strategies applied to What is lacking are data prov- ing that any particular management strategy prevents SCD. As a consequence, decisions regarding whether surgery is necessary or exercise restriction or medi- cal therapy might be beneficial are all based on syn- thesizing limited data and applying to an individual patient. Clinicians commonly extrapolate to assist in medical decision-making, but the consequences of Table 34. Factors That May Relate to the Clinical Importance of AAOCA and Risk of SCD Age AAOCA is more commonly invoked as the cause of SCD in patients <35 y of age than in patients >35 y of age, in whom atherosclerotic coronary disease becomes a more prevalent cause. However, death has been attributed to AAOCA in patients of all ages; there does not seem to be an age beyond which the AAOCA may not be relevant, even in the setting of atherosclerotic coronary disease and other concomitant conditions.S4.4.7-1,S4.4.7-2 Anatomy of coronary ostium and proximal coronary course Slit-like/fish-mouth-shaped orifice, acute angle takeoff, intramural course, interarterial course and hypoplasia of the proximal coronary artery have all been proposed as reasons for symptoms, ischemia and SCD in patients with AAOCA. The slit- like orifice is more commonly seen in anomalous right coronary artery arising from the left sinus. Each of these anatomic findings offers a pathophysiological mechanism for intermittent ischemia, particularly at times of high cardiac output and/or increased aortic wall tension, such as during exercise.S4.4.7-6,S4.4.7-9 S4.4.7-11 Anomalous origin Left coronary artery arising from the right cusp is less common than the right coronary artery arising from the left cusp but is more often found in autopsy series of SCD.S4.4.7-1,S4.4.7-3,S4.4.7-15 This suggests that anomalous origin of the left coronary artery from the right cusp is more likely to cause SCD than anomalous origin of the right coronary artery from the left cusp. This may be due either to anatomic features that make anomalous aortic origin of the left coronary artery prone to coronary compromise or because a larger proportion of myocardium is supplied by the left coronary artery, or both. Exercise Autopsy series suggest a most patients die during, or in close temporal association with, exercise.S4.4.7-3 S4.4.7-5 Ischemia Autopsy series demonstrate myocardial fibrosis in a significant number of patients whose deaths were attributed to AAOCA, particularly in patients with anomalous left coronary artery arising from the right cusp.S4.4.7-5 Surgical series describe patients with ischemia or MI before surgical repair in the absence of other CAD, suggesting a relation of the coronary anomaly to the ischemia.S4.4.7-16 This suggests that had perfusion imaging been obtained before SCD, ischemia would have been found in such patients.S4.4.7-17,S4.4.7-18 However, other data indicate that a normal stress test does not preclude a SCD event, with the proviso that most of those studies used only stress ECG, rather than the more sensitive and specific modalities of nuclear perfusion imaging or stress echocardiography. In addition, postoperative studies have shown that ischemia may be found after surgical repair in the distribution not supplied by the abnormal coronary artery and may not persist on repeat Symptoms In autopsy and surgical series, a significant number of patients reported cardiovascular symptoms, including before SCD events.S4.4.7-4,S4.4.7-7,S4.4.7-8,S4.4.7-20,S4.4.7-21 Symptoms are more commonly reported in patients in whom the left coronary artery arises from the right sinus. Surgical series have described improvement in symptoms after surgical AAOCA indicates anomalous aortic origin of the coronary artery; CAD, coronary artery disease; ECG, electrocardiogram; MI, myocardial infarction; and SCD, sudden cardiac death. CLINICAL STATEMENTS AND GUIDELINES being wrong for a young patient with AAOCA may be perceived to be greater than for many other con- ditions. Consequently, there is often a clinical urge to seek a reason to do something like surgical repair, because the available data do not identify clinical fea- tures that provide reassurance that a patient is at low risk of cardiovascular events. Unfortunately, evidence demonstrating that surgical repair ameliorates SCD risk, derived from large enough cohorts followed over a sufficient period of time, is not available. 4.4.7.1. Anomalous Coronary Artery Evaluation Recommendations for Anomalous Coronary Artery Evaluation Referenced studies that support recommendations are summarized in Online Data Supplement 51. COR LOE Recommendations Diagnostic I C-LD Coronary angiography, using catheterization, CT, or CMR, is recommended for evaluation of anomalous I C-LD Anatomic and physiological evaluation should be performed in patients with anomalous aortic origin of the left coronary from the right sinus and/or right coronary from the left sinus.S4.4.7.1-4 S4.4.7.1-9 Recommendation-Specific Supportive Text 1. CTA, CMR, and catheterization can all delineate the proximal course of the coronary artery and relationship to other structures. CTA is generally preferred because it has superior spatial and tem- poral resolution, although CMR may also pro- vide adequate delineation of the relationship of the coronary artery to the aorta, PA and other structures, including whether the proximal course appears to be intramural. Coronary angiography by catheterization can be helpful when there is concern about stenosis in the coronary artery or when concomitant hemodynamic evaluation for shunt assessment or intravascular ultrasonog- raphy/flow evaluation is needed. 2. Assessment of AAOCA is enhanced when the precise anatomy and physiological impact of the coronary artery anomaly are understood. As described in Table 34, the specific anomalous or- igin, anatomy of the orifice and proximal vessel and presence of ischemia may all influence the clinical course and thus the management options. Understanding these issues as precisely as pos- sible will better inform clinical decisions. Figure 5. Anomalous aortic origin of the coronary artery. *Surgical intervention to involve unroofing or coronary revascularization for patients with concomitant fixed obstruction. CLINICAL STATEMENTS AND GUIDELINES 4.4.7.2. Anomalous Aortic Origin of Coronary Artery Recommendations for Anomalous Aortic Origin of Coronary Artery Referenced studies that support recommendations are summarized in Online Data Supplement 51. COR LOE Recommendations Therapeutic I B-NR Surgery is recommended for AAOCA from the left sinus or AAOCA from the right sinus for symptoms or diagnostic evidence consistent with coronary ischemia attributable to the anomalous coronary IIa C-LD Surgery is reasonable for anomalous aortic origin of the left coronary artery from the right sinus in the absence of symptoms or IIa C-EO Surgery for AAOCA is reasonable in the setting of ventricular arrhythmias. IIb B-NR Surgery or continued observation may be reasonable for asymptomatic patients with an anomalous left coronary artery arising from the right sinus or right coronary artery arising from the left sinus without ischemia or anatomic or physiological evaluation suggesting potential for compromise of coronary perfusion (eg, intramural course, fish-mouth-shaped orifice, acute Recommendation-Specific Supportive Text 1. In patients with symptoms related to AAOCA, re- pair of the anomaly should alleviate symptoms. In autopsy and surgical series, cardiac symptoms are more common in patients with a left coronary ar- tery arising from the right coronary cusp. In au- topsy studies of patients who died because of an anomalous coronary artery, fibrosis is a common finding, suggesting that ischemia preceded the ter- minal event. However, there are patients in whom a SCD event occurred despite normal stress ECG, and consequently absence of ischemia is not reas- suring. Autopsy series show that many patients whose death is attributed to anomalous coronary arteries are young, thus management of patients should take age into account, with heightened concern about the risk of sudden death in younger 2. Anomalous left coronary from the right sinus is less common than anomalous right coronary from the but anomalous left coronary artery from the right is more commonly found in autopsy series of athletes and military recruits who had non- traumatic death than right coronary from the left The overrepresentation of the anomalous left coronary from the right sinus suggests a higher risk of SCD, particular at extremes of exertion and in patients <35 years of age. There are some anatomic features that are thought to be associated with increased risk of com- promise of coronary flow and/or SCD, including a fish-mouth-shaped or slit-like orifice, or intramural although the slit-like orifice is more commonly encountered in a right coronary arising from the left cusp. It is difficult to quantitate the ab- solute risk of SCD associated with anomalous aortic origin of the left coronary from the right sinus, and data demonstrating that surgery ameliorates the SCD risk have not been published. Until studies suggest otherwise, limited data and expert con- sensus suggest that it is reasonable that adults with this malformation should undergo surgical unroof- ing unless there are extenuating circumstances that would make surgery high risk. 3. In patients with ventricular arrhythmias presumed related to ischemia caused by anomalous origin of a coronary artery, repair is an option to alleviate the ischemia and presumably mitigate the recurrence of ventricular arrhythmias. However, care should be individualized, as there may be other factors (eg, CAD, cardiomyopathy, residual ischemia) contrib- uting to ventricular arrhythmias that warrant con- tinued vigilance and additional therapy. 4. Anomalous aortic origin of the right coronary from the left sinus is more common than anomalous aortic origin of the left coronary from the right sinus. The risk of SCD with the former malformation is difficult to quantitate. There is some physiological rationale to believe that asymptomatic patients without ev- idence of compromised blood flow would benefit from unroofing, but there are not data to demon- strate that surgical interventions alter the risk of SCD. Thus, watchful waiting may be an appropriate course as well, particularly for a patient with an anomalous right coronary arising from the left sinus. 4.4.7.3. Anomalous Coronary Artery Arising From the PA Recommendations for Anomalous Coronary Artery Arising From the PA Referenced studies that support recommendations are summarized in Online Data Supplement 51. COR LOE Recommendations Therapeutic I B-NR Surgery is recommended for anomalous left coronary artery from the PA.S4.4.7.3-1 S4.4.7.3-7 I C-EO In a symptomatic adult with anomalous right coronary artery from the PA with symptoms attributed to the anomalous coronary, surgery is recommended. IIa C-EO Surgery for anomalous right coronary artery from the PA is reasonable in an asymptomatic adult with ventricular dysfunction or with myocardial ischemia attributed to anomalous right coronary artery from the PA. CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. Surgery can include reimplantation of the left coronary artery directly into the aorta with or without an interposition graft. Ligation or clo- sure of the left coronary artery at the level of the PA with coronary artery bypass grafting can also be performed, usually using the left internal mammary artery anastomosed to the left anterior descending. 2. Surgery can include reimplantation of the right coronary artery directly into the aorta with or without an interposition graft. Ligation or clo- sure of the right coronary artery at the level of the PA with coronary artery bypass grafting can also be performed, usually using the right internal mammary artery anastomosed to the right coro- nary or posterior descending coronary artery. 3. Surgery to alleviate ischemia or ventricular dys- function is reasonable if the anomalous coronary artery is thought to be the cause. Surgery can in- clude reimplantation of the right coronary artery directly into the aorta with or without an interpo- sition graft. Ligation or closure of the right cor- onary artery at the level of the PA with coronary artery bypass grafting can also be performed, usually using the right internal mammary artery anastomosed to the right coronary or posterior descending coronary artery. 4.4.8. Coronary Artery Fistula Coronary artery fistula is an abnormal communication between a coronary artery and another cardiovascular Table 35. High-Impact Research Questions in ACHD General Pathophysiology What are the mechanisms of heart failure that can be prevented, reversed, or treated? Why does the systemic right ventricle fail? Will all patients with Fontan physiology develop clinically important cirrhosis, and how can we prevent this? Who is at risk of aortic rupture and dilation? Are patients with manipulated coronary arteries (eg, ASO, Ross repair) at risk of premature coronary artery disease? What is the impact of radiation exposure on long-term health? Can we predict who will develop pulmonary hypertension/pulmonary vascular disease? Medical and surgical treatment How can we modify current CHD surgical procedures to prevent or reduce later development of heart failure and/or arrhythmias? Which patients with ACHD can use direct oral anticoagulants instead of warfarin? What is the best algorithm for contraception choices? Beyond those with severe PAH, which patients will benefit from PAH therapies? Do patients with ACHD with systemic right ventricles and HF benefit from standard therapies (beta blockers, ACE inhibitors/ARBs, aldosterone antagonist)? Which one(s)? What medical therapies benefit patients with failing Fontan physiology? Do asymptomatic patients with ACHD with PAH benefit from PAH-specific therapy? Who will benefit from ventricular assist devices? What should be the threshold(s) for aortic aneurysm surgery? What pacing and resynchronization strategies are of most benefit, and when should they be used? Outcomes/risk assessment What criteria should determine transplantation eligibility? Which patients benefit from primary prevention ICDs? How can we risk stratify for SCD in patients with systemic right ventricles? What operative risk score predicts outcomes in ACHD reoperations? What HF risk score predicts outcomes in patients with ACHD? Is there a level of exercise where risk exceeds benefit? What is the rate and/or risk of endocarditis? Assessment Who is at high risk of neurodevelopmental abnormalities and would benefit from neuropsychiatric evaluation and treatment? Who should be screened for anxiety and depression, what treatment is most effective, and are there differences compared with non- patients with ACHD? What is the standard protocol for assessing right ventricular size and function by CMR imaging? Which biomarkers are predictive of mortality and morbidity? (Continued) CLINICAL STATEMENTS AND GUIDELINES structure, which may include a cardiac chamber, coro- nary sinus, superior vena cava, or PA. The incidence of coronary artery fistula is 0.1% to 0.2% in all patients undergoing coronary angiography.S4.4.8-1,S4.4.8-2 Fistulous communications may be congenital or acquired. Spe- cific management strategies, which can include surgical repair or catheter embolization, have been controver- sial. In a series of 46 patients treated with surgery, pre- dominant preoperative symptoms included angina and Importantly, postoperative myocardial infarc- tion occurred in 11% because of low flow in the dilated coronary artery proximal to fistula closure. Late survival was also significantly reduced compared with an age- matched population. The presence of coronary artery fistula(s) requires review by a knowledgeable team that may include congenital or noncongenital cardiologists and surgeons to determine the role of medical therapy and/or percutaneous or surgical closure.S4.4.8-3 Disease-specific Coarctation of the aorta Which measure of hypertension resting, exercise, or ambulatory best predicts outcomes? Is there an optimal antihypertensive regimen? What should blood pressure goals be? How often should patients be screened for thoracic aneurysm? Should exercise-induced hypertension be treated? What criteria warrant reintervention in recoarctation? Is long-term outcome better with medical therapy or catheter intervention for less than severe recoarctation? Should patients be screened for intracranial aneurysm, and if so, how often? Ebstein anomaly What is the indication for surgery in the asymptomatic patient? Who should have a Glenn shunt at the time of tricuspid valve surgery? Should surgeons attempt tricuspid valve repair or routinely perform replacement in all patients? TOF What is the optimal timing for pulmonary valve replacement in asymptomatic patients with TOF? Do pulmonary valve replacement and ventricular tachycardia ablation decrease the risk of SCD? Who needs a primary prevention ICD, and does this strategy reduce mortality? Is there a role for PAH therapies in TOF? Why does left ventricular dysfunction develop? TGA/systemic right ventricle Who benefits from ACE inhibitors/ARBs/beta blockers/spironolactone? Who needs a primary prevention ICD, and does this strategy prevent mortality? What imaging findings predict mortality/morbidity? In CCTGA with VSD/PS, does the double switch have better long-term outcomes than VSD closure and left ventricle to-PA conduit? When should tricuspid valve replacement be performed? What is the role of cardiac resynchronization therapy in patients with systemic right ventricle? ASO What are the long-term outcomes after ASO? How should the possibility of asymptomatic coronary disease (ostial, compression) and ischemia be assessed? Single ventricle/ Fontan Is warfarin or aspirin beneficial in patients with a Fontan? Are PAH therapies beneficial? Is exercise capacity predictive of mortality? What liver screening is appropriate and at what intervals? How is protein-losing enteropathy best medically treated? Why do some patients fail with preserved ejection fraction, whereas other have decreased ejection fraction? What are the long-term outcomes of hypoplastic left heart syndrome? What is ideal timing for heart transplantation in single ventricle Fontan patients, and should liver issues prompt earlier transplantation than might be felt necessary from a cardiac perspective? Which has better long-term outcomes, the Fontan operation or bidirectional Glenn alone? Coronary anomalies Does surgical intervention in anomalous aortic origin of coronary arteries improve survival? ACE indicates angiotensin-converting enzyme; ACHD, adult congenital heart disease; ARB, angiotensin-receptor blocker; ASO, arterial switch operation; CCTGA, congenitally corrected transposition of the great arteries; CHD, congenital heart disease; CMR, cardiac magnetic resonance; ICD, implantable cardioverter- defibrillator; HF, heart failure; PA, pulmonary artery; PAH, pulmonary artery hypertension; PS, pulmonary stenosis; SCD, sudden cardiac death; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; and VSD, ventricular septal defect. Table 35. Continued CLINICAL STATEMENTS AND GUIDELINES 5. EVIDENCE GAPS AND FUTURE DIRECTIONS There are multiple challenges to developing evi- denced-based care for patients with ACHD. The heterogeneity of conditions leads to small numbers of specific ACHD populations from which to derive guidelines. Additionally, lack of infrastructure to track prevalence, fragmented care systems, loss to follow-up, and changes in treatment strategies over time all contribute to the challenges of developing Comprehensive multicenter and pop- ulation registries and databases are needed to have adequate numbers of patients to address clinical questions. Novel study methodologies are needed to ascertain effectiveness of diagnostic and therapeutic options when each disease is sufficiently rare and e- vents occur over sufficiently long periods that RCTs are impractical. Although there are data that patients with complex CHD have improved survival when cared for at an ACHD center, how can networks of care be developed that ensure patients get the ex- pert care needed when there are inadequate number of ACHD cardiologists and ACHD centers? How do we ensure that patients are not lost to care as they transition from pediatric to adult cardiology? How do we ensure that patients with ACHD who would ben- efit from heart transplantation receive accurate listing priority? See Table 35 for a collection of high-impact research questions in ACHD. ACC/AHA TASK FORCE MEMBERS Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T. O Gara, MD, MACC, FAHA, Chair-Elect; Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair; Nancy M. Albert, PhD, RN, FAHA*; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Joshua A. Beckman, MD, MS, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA*; Ralph G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA*; Anita Deswal, MD, MPH, FACC, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel S. Gidding, MD, FAHA*; Zachary D. Goldberger, MD, MS, FACC, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; Jos Joglar, MD, FACC, FAHA; Richard J. Kovacs, MD, FACC, FAHA*; Laura Mauri, MD, MSc, FAHA; E. Magnus Ohman, MD, FACC*; Mariann R. Piano, RN, PhD, FAHA, FAAN; Susan J. Pressler, PhD, RN, FAHA*; Barbara Riegel, PhD, RN, FAHA; Frank W. Sellke, MD, FACC, FAHA*; Win-Kuang Shen, MD, FACC, FAHA*; Duminda N. Wijeysundera, MD, PhD PRESIDENTS AND STAFF American College of Cardiology C. Michael Valentine, MD, FACC, President Cathleen C. Gates, Interim Chief Executive Officer and Chief Operating Officer William J. Oetgen, MD, MBA, FACC, Executive Vice Presi- dent, Science, Education, Quality, and Publishing MaryAnne Elma, MPH, Senior Director, Science, Educa- tion, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/ American Heart Association Katherine A. Sheehan, PhD, Director, Guideline Strategy and Operations Abdul R. Abdullah, MD, Senior Manager, Guideline Science American Heart Association Ivor Benjamin, MD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medical Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Prashant Nedungadi, PhD, Science and Medicine Advi- sor, Office of Science Operations Jody Hundley, Production and Operations Manager, Sci- entific Publications, Office of Science Operations ARTICLE INFORMATION This document was approved by the American College of Cardiology Clinical Policy Approval Committee in May 2018, the American Heart Association Sci- ence Advisory and Coordinating Committee in June 2018, and the American Heart Association Executive Committee in July 2018. The Comprehensive RWI Data Supplement table is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIR.0000000000000603. The online Data Supplement is available with this article at https://www. ahajournals.org/doi/suppl/10.1161/CIR.0000000000000603. This article has been copublished in the Journal of the American College of Cardiology. Copies: This document is available on the websites of the American College of Cardiology (www.acc.org) and the American Heart Association (professional. heart.org). A copy of the document is also available at https://professional.heart. org/statements by selecting the Guidelines & Statements button. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guide- lines development, visit https://professional.heart.org/statements. Select the Guidelines & Statements drop-down menu near the top of the webpage, then click Publication Development. Permissions: Multiple copies, modification, alteration, enhancement, and/ or distribution of this document are not permitted without the express permis- sion of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the Copyright Per- missions Request Form appears in the second paragraph (https://www.heart. org/en/about-us/statements-and-policies/copyright-request-form). * Former Task Force member; current member during the writing effort. CLINICAL STATEMENTS AND GUIDELINES REFERENCES PREAMBLE P-1. Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Institute of Medicine (US). Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press, 2011. P-2. 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