Targeted Pulmonary Arterial Hypertension Therapies and a Combined Medical-Surgical Approach for Congenital Heart Disease Patients
Pulmonary arterial hypertension (PAH) with increased pulmonary vascular resistance (PVR) is a frequent complication of congenital heart disease (CHD), most commonly occurring with systemic-to-pulmonary shunt lesions. The natural disease progression involves pulmonary endothelial damage due to exposure to increased pulmonary blood flow and pressure, and in its most severe form results in Eisenmenger syndrome (ES), in which there is shunt reversal and cyanosis. Due to anatomic and histopathologic similarities of PAH in patients with CHD, as well as those with idiopathic and other forms of Group 1 PAH, there is an evolving interest and role for the use of the newer targeted PAH therapies in CHD patients. While early closure of shunt lesions is the best preventive measure, the use of targeted medical therapies when a patient is too high risk for surgery, following surgical repair, and even in those with reversal of shunting due to advanced disease, has emerged over the past decade.
Pulmonary arterial hypertension with increased PVR is a frequent complication of CHD, known as associated pulmonary arterial hypertension (APAH)-CHD.12 This results from pulmonary vascular remodeling due to nonrestrictive, shunt-related increases in pulmonary blood flow (PBF) and/or exposure to increased pulmonary artery pressure (PAP) and sheer stress.3 While the currently accepted definition of PAH no longer includes elevated PVR, it is very important to determine PVR when evaluating a patient with APAH-CHD, as an isolated elevation in PAP with normal PVR may occur with increased PBF and can be amenable to surgery as opposed to representing true pulmonary vasculopathy. Therefore, these authors continue to use the classic definition of PAH when evaluating APAH-CHD, which includes a mean PAP ≥25 mm Hg with normal left-sided filling pressures (left ventricular end-diastolic pressure or pulmonary capillary wedge pressure ≤15 mm Hg) and an elevated PVR (PVR indexed to body surface area [PVRI] >3 Wood units [WUxm2]).4–6 In cases of APAH-CHD, it is also important to differentiate PAH from pulmonary venous hypertension, in which there is increased PAP in the setting of elevated left-sided filling pressures and normal PVR, or a mixed picture with elevation of PAP, left-sided filling pressures, and also PVR. It is critical to distinguish between patients with PAH, pulmonary venous hypertension, and mixed disease (PAH/PVH), as the treatments for these various forms of disease not only vary, but targeted medical therapies may be unsafe in patients with associated postcapillary pulmonary hypertension.
As more patients with CHD are surviving into adulthood, APAH-CHD has become an important medical management issue. The development of PAH in the setting of CHD is partly dependent on the type and size of the cardiac defect, as well as other predisposing environmental and genetic factors. Post-tricuspid valve lesions such as ventricular septal defect (VSD) and patent ductus arteriosus (PDA) are more prone to the development of PAH than pre-tricuspid valve lesions such as atrial septal defect (ASD).7 With progression of disease in these patients, cyanosis eventually develops as a result of reversal of left to right shunting, and this is known as Eisenmenger syndrome.7 It is generally believed that in order to avoid the development of pulmonary vascular disease (PVD), nonrestrictive posttricuspid defects such as large VSDs and PDAs should be repaired prior to 1 or 2 years of age, while ASDs may be repaired later in childhood. In addition, there are more complex cardiac defects that are associated with the early development of PAH. These include truncus arteriosus, transposition of the great vessels (especially in the presence of a VSD), and complete atrioventricular septal defect (especially in the setting of trisomy 21). If these defects are not repaired within the first few weeks of life, severe PVD will almost invariably develop.8
The clinical presentation of APAHCHD can be divided into 4 physiologic subtypes (Table). This clinical classification becomes very important in the management of these patients, as treatment strategies are not necessarily the same for each subtype. The latter 2 categories, PAH in the setting of small defects and PAH after corrective cardiac surgery, are physiologically analogous to idiopathic PAH (IPAH), with respect to the lack of an adequate “pop-off” for the failing right ventricle (RV). These patients are likely at increased risk for more rapidly progressive RV failure and worse outcomes than those patients with adequate RV “pop-off.” The medical approach in these patients does not differ from that of other forms of WHO Group 1 PAH, although there are less controlled data on the use of targeted PAH therapies available for such patients.
During the last 2 decades there have been significant improvements in the treatment and outcomes of patients with WHO Group 1 PAH. Nine medications have become available in the United States to target 3 main pathways involved in the pathophysiology of PAH: the prostacyclin, endothelin, and nitric oxide pathways, and treatment options now span the oral, inhaled, subcutaneous, and intravenous routes. Much of the initial testing occurred in small observational trials of APAH-CHD or in patients with Group 1 PAH; however, only a small number of the Group 1 patients included in many of the early landmark trials were APAHCHD patients. In 1999, Rosenzweig et al reported on the benefits in functional capacity and hemodynamics of long-term intravenous epoprostenol in patients with APAH-CHD,9 and Simonneau et al reported similar benefits of subcutaneous treprostinil following a 12-week randomized, double-blind, placebo-controlled trial in which 109 of 470 enrolled patients either had repaired or unrepaired congenital shunt lesions.10 The early, randomized, double-blind, placebo-controlled trials involving the phophodiesterase-5 inhibitors sildenafil (SUPER-1 trial) and tadalafil (PHIRST trial) included 7% and 12% APAH-CHD patients (either ASD or repaired shunt lesions).1112 Although the earlier trials involving the endothelin receptor antagonists bosentan and ambrisentan did not include APAH-CHD patients, the first randomized, double-blind, placebo-controlled drug trial solely on ES patients was the BREATHE-5 trial involving bosentan, published in 2006.13 Due to the similarities in histopathology and pathophysiology within WHO Group 1 PAH patients, including those with IPAH and APAH-CHD, the targeted PAH therapies are often used in the treatment of APAH-CHD patients, as well. However, the absence or small percentage of APAH-CHD patients included in these drug trials underscores the need for future studies designed specifically to study this heterogeneous patient population. Medical management of APAH-CHD patients within the first 2 subtypes of APAH-CHD (Table), those with ES and those with PAH in the setting of unrepaired moderate to large defects, requires additional attention to the impact of residual shunting on medical management. The clinical picture within these groups of patients spans a wide range, and at either end of the spectrum, medical decision making is relatively straightforward. At one end, an infant with a large nonrestrictive VSD will have elevated PAP and normal PVRI (≤3 WUxm2), and can be treated with surgical closure of the shunt with little fear that PAP will remain elevated postoperatively. On the opposite end of the spectrum are patients with severe pulmonary vasculopathy, or ES, demonstrated by shunt reversal, low PBF, and cyanosis in the setting of elevated PAP and high PVR. In these patients with significantly elevated PVR and reversal of shunting, surgical closure would not be advisable; however, these patients may benefit from some of the newer targeted PAH medical therapies.13–16 With advances made in targeted PAH therapies, the concept of a combined medical-surgical approach has also become more feasible for subgroup 2 patients (PAH with moderate to large defects in whom PVR is at least mildly increased, systemic-to-pulmonary shunt is still prevalent, and no cyanosis is present at rest), with optimization first medically prior to consideration of surgery. In addition, the idea of a partial repair has emerged in which a fenestration, most commonly an interatrial communication, is left by the surgeon to serve as a “pop-off valve” for the RV.8 This determination of operability is one of the more challenging and more important aspects of the management of patients with APAH-CHD.
PAH ASSOCIATED WITH CONGENITAL SYSTEMIC TO PULMONARY SHUNTS: PREEISENMENGER SYNDROME
For patients with APAH-CHD in the second physiologic subgroup (Table) with mildly to moderately elevated PVR and moderate to large increases in PBF, the determination of operability is based on whether PAH will improve or progress following surgery. While there is no accepted protocol or algorithm to make this determination, a vital tool at the disposal of the cardiologist in such cases is the cardiac catheterization. Although no validated criteria exist for predicting postoperative morbidity and mortality, a complete set of hemodynamics should be obtained, along with acute vasodilator testing and possible balloon occlusion of the defect. In IPAH patients, the most prognostic catheterization data are indices of right heart function, such as cardiac index and right atrial pressure,17 and PAP is generally less useful for assessing disease severity and prognosis, as it may in fact decrease with worsening right heart failure, due to the RV's inability to generate higher pressure. In shunt lesions, it is important to realize that by having a nonrestrictive VSD or PDA, PAP will be at systemic levels regardless of the PVR. In order to evaluate the degree of PVD, it is important to examine PVR, the ratio of PVR to systemic vascular resistance (SVR), and the ratio of pulmonary to systemic blood flow. In pediatrics, by convention, PVR is indexed to body surface area (PVRI) to allow for a more direct comparison of hemodynamics between disparately sized patients.18
During evaluation of a systemic-to-pulmonary shunt, if there is no evidence of pulmonary venous hypertension once baseline data are collected and PVRI is >3 WUxm2, acute vasodilator testing should be performed with inhaled nitric oxide or intravenous epoprostenol, during which another full hemodynamic assessment should be performed. Separate assessment with 100% oxygen may be performed, as well. An extensive review of hemodynamic parameters in determining operability in APAH-CHD was recently published by Giglia and Humpl.19 The authors acknowledged limitations to many of the studies reviewed, and were clear that any parameters be used as a guide within the context of the complete clinical picture. PVRI values in the range of 6 to 8 WUxm2 or lower are generally considered operable.19 The ability to lower PVRI to 6 WUxm2 or lower with vasodilator testing with inhaled nitric oxide +/− oxygen has been associated with better outcomes, as well.20–22 Additionally, a >10% decrease in PVR and PVR/SVR ratio in response to acute vasodilator testing, with a final PVR/SVR ratio of <0.3 are predictive of better postoperative outcomes.2324
Due largely in part to advances in targeted PAH therapies and studies demonstrating improved hemodynamics in APAH-CHD patients with such therapies, there is an evolving role for a combined medical-surgical approach to those patients that are either borderline operable, or in some cases initially inoperable.25–28 It is reasonable to treat with targeted therapies for a period of months and reevaluate by catheterization, sometimes requiring serial reevaluations. If medical treatment of a patient with a shunt and moderate PVD is effective, PVR will lower and result in increased PBF. As a result, surgical measures may actually be necessary to protect the pulmonary vasculature from the development of further damage.
Cardiac catheterization alone, however, cannot determine operability, since catheterization data are often obtained under “ideal” resting conditions. While a patient at rest may seem to be operable, with a minor respiratory illness and hypoxic vasoconstriction, it may become evident that a shunt should not be closed, or at least not completely. A thorough medical history and physical examination, and exercise testing when possible, play important roles in the determination of operability. Important elements of the history include age, type of CHD, and time of and circumstances surrounding diagnosis. The importance of the type of CHD has been previously discussed; and in general, the earlier a shunt lesion is diagnosed, the more likely the patient is operable. In addition, a history of cyanosis and/or dyspnea with exertion is important. Signs of cyanosis such as blue lips or nail beds with exercise, clubbing, and erythrocytosis also help provide a complete picture to determine operability.
EISENMENGER SYNDROME
In 1897, Viktor Eisenmenger first described a 32-year-old patient who died of massive hemoptysis and had a VSD on postmortem examination. The term “Eisenmenger syndrome” was coined by Paul Hamilton Wood in 1958 to define the condition of increased PAP and PVR in relation to a VSD with resultant shunt reversal and cyanosis. Subsequently, ES has been used to describe any CHD or shunt between the great arteries with resultant increase in PVR and shunt reversal.29 Advances in CHD diagnosis and cardiac surgery, especially during infancy and early childhood, have helped to increase the number of CHD patients surviving into adulthood, and decrease the number of patients with ES in the Western world. Only around 5% of adults with CHD will develop PAH.30 However, in developing countries where patients seek medical care later in life, ES still remains a significant problem. The worldwide prevalence of PAH in adults with CHD has recently been estimated at between 1.6 and 12.5 million, with 25% to 50% presenting with ES.31 In Latin America, the prevalence of advanced APAH-CHD relative to IPAH at cardiovascular centers is between 2:1 and 3:1.32
Although life expectancy is reduced in ES, it is significantly better than IPAH, with many patients surviving into their third and fourth decades,33 and even some into their seventh decade.3334 More than 40% of subjects are expected to be alive 25 years after diagnosis.735 There is some bias in these data as many patients were from the era prior to targeted PAH therapies. As a result, many who died early of severe hypoxemia and RV failure due to advanced ES may not have been included. However, with advances in targeted therapies, the hope is for future improvements to these numbers, supported by a recent study predicting 5-year survival of 95.3% in children with ES.36
Conventional Therapies for Eisenmenger Syndrome
Historically, treatment options for ES patients had been limited to palliative therapies and heart-lung transplantation or lung transplantation with surgical correction of a simple shunt. Currently, conventional management is used in combination with targeted PAH therapies. Commonly used conventional therapies may include digoxin, diuretics, and anticoagulation, as well as antiarrhythmics when warranted, although none of these agents have been shown to improve survival in ES. Although supporting evidence is not particularly strong, digoxin is generally used for right heart failure.37 Diuretics are often employed in this situation, as well; however, they should be used cautiously, as they may reduce plasma volume in patients with erythrocytosis, and also lead to dehydration. Anticoagulation in ES patients is a debatable subject due to increased risks of pulmonary artery thrombosis as well as hemoptysis, stroke, and hemorrhage.37 Although the benefit of anticoagulation in IPAH patients has been demonstrated,3839 no such data exist in ES patients. Given the potential complications, the decision to anticoagulate should be made carefully on an individual, case-by-case basis. Long-term use of oxygen is often employed in ES patients; and while it may be associated with improvement in subjective status, no survival benefit has been reported.3740
ES patients that are chronically cyanotic may develop secondary erythrocytosis. With hemoglobin above 20 g/dL, hyperviscosity symptoms may develop, including headache, fatigue, and difficulty concentrating. Phlebotomy, combined with isovolumic fluid replacement, is reserved only for patients with symptomatic hyperviscosity and no iron deficiency or dehydration.4142 Iron deficiency, often missed in this patient population due to the requirement of a relatively high resting hemoglobin in the setting of chronic cyanosis, is associated with lower event-free survival and higher mortality in ES patients, and should be treated when recognized.4143
Targeted Therapies for Eisenmenger Syndrome
There are emerging data on the use of all 3 main classes of targeted PAH therapies (prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors) for the treatment of ES patients. As opposed to APAH-CHD with moderate PVD, ES patients are unlikely to experience a significant decrease in PVR that would be enough to reverse shunting and allow for surgical correction of CHD. The aim of targeted therapies in these cases is to improve exercise tolerance, hypoxemia, physical capacity, and ultimately survival.
Intravenous epoprostenol has been used in pediatric PAH,44 and specifically in APAH-CHD,945 leading to improvements in functional capacity, hemodynamics, and survival. In 1999, Rosenzweig et al reported the first benefit of PAH-targeted therapy of any form in this patient population, with improvements in cardiac index, PVR, and quality of life in 20 patients with APAH-CHD.9 Similarly, in 2003, Fernandes et al demonstrated improvements in functional capacity, oxygen saturation, and hemodynamics in 8 ES patients using epoprostenol.45 Treatment with epoprostenol requires use of a permanent central venous catheter, which can be problematic in the setting of right to left shunt due to the potential for thromboembolic events. In addition, systemic and local complications may include infections, sepsis, and line breakage with drug interruption. Treprostinil, a similar and longer-acting prostanoid, can be delivered either intravenously, subcutaneously, or by inhalation, and offers potential advantages over epoprostenol in terms of a longer half-life and mode of delivery. Although efficacy and safety has not been fully established in this patient population, open-label multicenter trials involving the intravenous and subcutaneous formulations have included patients with APAH-CHD,1046 and the inhaled formulation has recently been FDA-approved for use in patients in WHO Group 1.
The first randomized, double-blind, placebo-controlled study in ES patients was the BREATHE-5 trial, which investigated the efficacy and safety of the dual endothelin receptor antagonist bosentan in adult ES patients.13 It remains the only trial of its kind dedicated solely to the ES population. During the 16-week study, bosentan significantly reduced PVR and improved PAP and exercise capacity compared to placebo.13 Longer-term data from the follow-up portion of the study demonstrated continued improvements in exercise capacity and functional class over an additional 24 weeks.15 Safety findings were of particular importance, given the potential for worsening of right to left shunting in the face of decreased SVR with vasodilator therapies. There was no significant difference in oxygen saturation change between the bosentan and placebo groups during the study period. In addition, there was a worsening of PVR in the placebo group, underscoring the progressive nature of untreated ES. Smaller-scale, open-label studies demonstrate sustained effects over longer periods of time using bosentan in the ES population.47–49 The selective endothelin receptor antagonist ambrisentan offers potential advantages over bosentan given its selectivity for the endothelin-A receptor, which demonstrates vasoconstrictor effects. Although less studied, ambrisentan has also been noted to be safe and efficacious in APAH-CHD and ES.28
Oral sildenafil is the most widely used of the phosphodiesterase-5 inhibitors in the treatment of PAH, and has been used in pediatrics and APAH-CHD, with benefits on exercise capacity and hemodynamics demonstrated.265051 Singh et al performed a randomized, placebo-controlled, double-blind, crossover study in 10 IPAH and 10 ES patients in 2006, and found that sildenafil significantly improved functional status, exercise capacity, and PAP compared to placebo.50 Similarly, a recent prospective, open-label, multicenter study out of China on 84 ES patients demonstrated safety and improved functional status, exercise capacity, oxygen saturation, PAP, and PVR after 12 months of sildenafil therapy.14 Sildenafil also comes in an intravenous form, and there may be a role for its use perioperatively in the intensive care setting. The longer-acting, once-daily dosed tadalafil is less well studied than sildenafil; however, a recent randomized, placebo-controlled, double-blind, crossover study in ES patients also demonstrated safety and short-term improvements in exercise capacity, functional class, oxygen saturation, and hemodynamics after 6 weeks of therapy.52
Due to the progressive nature of PAH and the efficacy limitations of each of the drug classes, one of the mainstays of the treatment of PAH has become combination therapy. In this manner, drugs with different mechanisms of action may provide an additive effect, or even the same effect at lower doses. Although data are limited in ES patients, in 2010, Iversen et al performed a randomized, placebo-controlled, double-blind, crossover study evaluating the effect of combination therapy with bosentan and sildenafil in 21 ES patients.53 In this study, patients were treated with bosentan for 9 months and were then treated for 3 months with sildenafil or placebo, followed by a 3-month crossover. They found improvements in exercise capacity and hemodynamics after treatment with bosentan, but no further benefit after addition of sildenafil, although there was an increase in oxygen saturation and the combination was well tolerated. The future of PAH therapy in ES patients certainly involves evaluation of such combination therapies, as well as studies evaluating cutting-edge, targeted PAH therapies such as oral prostacyclin (selexipag), tissue-targeting endothelin receptor antagonist (macitentan), receptor tyrosine kinase antagonist (imatinib), and soluble guanylate cyclase inhibitor (riociguat).54 Over the last decade, the outlook for the ES patient has gone from a “hands-off” strategy to a hopeful one, in the form of targeted PAH agents that may lead to improvements in functional status, exercise capacity, and survival. Further study in clinical trials will be essential for optimization of medical therapies for APAH-CHD over the next decade.
CONCLUSIONS
While PAH associated with CHD is classified with many other subgroups as Group 1 pulmonary hypertension, this group is very heterogeneous in terms of anatomic, physiologic, and clinical features. Improvements in diagnosis and surgery for CHD have dramatically improved the short- and long-term outlook for patients with APAH-CHD. Although advancements in noninvasive imaging such as echocardiography have helped in the evaluation of this patient population, the importance of cardiac catheterization cannot be overstated in helping with management. In addition, the newer targeted PAH therapies appear to have short-term benefits in these patients, but require further investigation, and their use in patients with borderline hemodynamics has paved the way for a combined medical-surgical approach to management in select patients.
Contributor Notes