Pulmonary Arterial Hypertension Medical Management of the Adult Patient with Congenital Heart Disease

Abstract

Congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) includes a heterogeneous patient population that can be characterized by the underlying cardiac malformation. CHD-associated PAH has an estimated prevalence of 5–10% in adult patients, with an increasing number of patients surviving to adulthood because of advances in the surgical management and the development of pulmonary arterial hypertension (PAH)-targeted pharmacotherapy. Although limited data exist, targeted PAH pharmacotherapy has proven to be beneficial in patients with CHD-associated PAH, with observed improvement in functional class, increase in exercise capacity, and improvement in quality of life and cardiopulmonary hemodynamics. Additionally, there has been increasing interest in the “treat-to-close” strategy. PAH-targeted pharmacotherapy may be used to optimize cardiopulmonary hemodynamics so as to improve patients’ operability in repairing the cardiac defect. Although there have been significant advances in the management of this disease state in the past 2 decades, mortality remains high, and ongoing clinical trials are needed to better understand the treat-to-close strategy.

Main article text

Introduction

Pulmonary arterial hypertension (PAH) is defined by a mean pulmonary arterial pressure of 25 mmHg or greater at rest with a pulmonary capillary wedge pressure of 15 mmHg or less and a pulmonary vascular resistance (PVR) of more than 3 Wood units (WU) [1]. Patients with congenital heart diseases (CHDs) represent a heterogeneous patient population because of the differences in underlying cardiac defects. CHD-associated PAH is a well-recognized entity that may develop during infancy through adulthood. Secondary to this, CHD-associated PAH has important prognostic implications because of the associated increased risk of morbidity and two-fold increase in mortality [2]. Recent advancements in medical management of PAH in the past 2 decades include the development of PAH-specific therapies that have been associated with improved outcomes; however, limited evidence exists supporting the role of PAH-specific therapies in patients with CHD-associated PAH.

Epidemiology, Pathophysiology, and Classification

With more than 90% of children with CHD reaching childhood, there is an increased prevalence of adult patients with CHD [3, 4]. It is estimated that with the growing CHD population, approximately 5–10% of adult patients with CHD will develop PAH [5–7]. Pulmonary hypertension may occur in patients with CHD because of increased pulmonary blood flow in the setting of systemic-to-pulmonary shunt, increased PVR, or passive venous congestion, or as the result of the combination of these conditions. The end result is a pulmonary arteriopathy and increased PVR similar to that seen in patients with idiopathic PAH. If left untreated, the increasing PVR will surpass the systemic vascular resistance, resulting in reversal of shunt flow (right to left) and the development of Eisenmenger syndrome [8].

The most up-to-date classification of pulmonary hypertension categorizes CHD-associated PAH as a subgroup of group 1 PAH [9]. The severity of PAH is dependent on the cause of CHD; for example, a higher number of patients with unrepaired ventricular septal defects (VSDs) will end up developing Eisenmenger syndrome and eventually PAH compared with patients with unrepaired atrial septal defects (ASDs) [10]. The most recent Nice symposium (2013) classified CHD-associated PAH under four separate phenotypes: (1) Eisenmenger syndrome; (2) left-to-right shunts (correctable and uncorrectable); (3) PAH with coincidental small cardiac defects (ASD <2 cm and VSD <1 cm) that themselves do not account for the development of PAH; (4) PAH that persists or develops after surgical correction of CHD [9]. Of the four phenotypes, patients with postoperative CHD-associated PAH have the worst prognosis, with survival rates similar to those seen in idiopathic PAH [11, 12].

Diagnosis

Patients often present with progressive dyspnea with exertion, increased fatigue, lower extremity swelling, and in some cases cyanosis [13]. Echocardiogram is often performed initially in the evaluation of pulmonary hypertension to help define the underlying anatomical abnormalities and estimate the right ventricular systolic pressures. An echocardiogram may also identify other markers of elevated pulmonary pressures, such as dilatation of the right cardiac chambers and right ventricular systolic dysfunction. In some cases, cardiac magnetic resonance imaging is performed to more clearly delineate the cardiac defects and provide further measures of right-sided heart function. A diagnosis of PAH can be made only by right-sided heart catheterization in which precapillary pulmonary hemodynamics are observed [1].

Treatment of CHD-Associated PAH

Patients with CHD-associated PAH should be referred to and treated at tertiary centers experienced in treating this unique subpopulation [14]. The literature has shown that adult patients with CHD-associated PAH have improved survival and outcomes if they are treated at tertiary centers and are more likely to receive PAH-specific therapies [15, 16]. Treatment with PAH-specific therapies in patients with Eisenmenger syndrome has been independently associated with improved survival [17]. PAH-specific pharmacotherapy is targeted at the three pathophysiologic pathways: the nitric oxide pathway, the endothelin pathway, and the prostacyclin pathway. The CHD-associated PAH population is largely underrepresented within PAH pharmacotherapy clinical trials, thus making it difficult to extrapolate general PAH results to all patients with CHD-associated PAH. That being said, several small, observational trials support the use PAH-specific therapies among patients with Eisenmenger syndrome and other causes of CHD-associated PAH [18, 19].

Pharmacotherapy targeted at the nitric oxide pathway includes the phosphodiesterase 5 inhibitors sildenafil and tadalafil, as well as the soluble guanylate cyclase stimulator riociguat. In the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) trial, CHD-associated PAH patients constituted 6% of the study population. Overall, patients treated with sildenafil experienced a reduction in functional class, increase in exercise capacity, and improvement in hemodynamics compared with patients who received placebo but data with regard to CHD-associated PAH were not available [20]. Additional literature supports the use of sildenafil in CHD-associated PAH, with favorable effects on functional class, exercise capacity, and hemodynamics (Table 1) [21–24]. Similar favorable results were seen in response to tadalafil [25, 26]. In Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1), patients with CHD-associated PAH with closed defects constituted 8% (n=35) of the population studied. These patients experienced reduction in functional class, increase in exercise capacity, increase in time to clinical worsening, and improvement in hemodynamic parameters [27]. Similarly to the SUPER-1 trial, CHD-specific outcomes were not available, but there was an overall improvement.

Table 1

Studies Evaluating the Effects of Sildenafil on Patients with Congenital Heart Disease–Associated Pulmonary Arterial Hypertension.

Study	Patients	Study type	6MW	Hemodynamics
Singh et al. [21]	Eisenmenger syndrome	Randomized double blind placebo-controlled crossover study	6MW distance increased by 96.9±11.3 m compared with the baseline (P=0.0001) and by 65.5±11.0 m compared with placebo (P=0.0001)	mPAP changed by −20.6±2.9 mmHg compared with the baseline (P=0.0001) and by −16.6±2.2 mmHg compared with placebo (P=0.0001)
Tay et al. [22]	Eisenmenger syndrome	Prospective open-label nonrandomized study	Baseline 347.3±80.7 m, after 3 months of therapy 392.5±82.0 m (P=0.002)	Not reported
Zhang et al. [23]	Eisenmenger syndrome	Prospective open-label multicenter study	Mean increase of 56 m (P≤0.0001)	Change in mPAP of −4.7 mmHg (−7.5 to −1.9 mmHg)
Chau et al. [24]	Eisenmenger syndrome vs. IPAH	Prospective open-label study	No significantly significant difference	Change in mPAP of −17±13 mmHg in Eisenmenger syndrome vs. +1.5±4.4 mmHg in IPAH (P=0.009)

IPAH, idiopathic pulmonary artery hypertension; mPAP, mean pulmonary artery pressure; 6MW, 6-minute walk.

Pharmacotherapy targeted at the endothelin pathway includes endothelin receptor antagonists such as bosentan, ambrisentan, and macitentan. Bosentan use in Eisenmenger syndrome resulted in favorable response with regard to exercise capacity and hemodynamics in the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) (Table 2). The response to treatment does not depend on the location of the defect [28, 32]. In the treatment arm, 65% of patients (n=24) had VSDs, 22% (n=8) had ASDs, and 14% (n=5) had both VSDs and ASDs. Other studies also confirmed favorable responses to bosentan (Table 2) [29–32]. Ambrisentan has been associated with increase in the 6-minute walk test distance in patients with CHD-associated PAH at 6 months [33]. The Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial included 8.4% of patients (n=62) with CHD-associated PAH. The study investigators observed reduced morbidity and mortality with treatment with macitentan (Table 3) [34]. Additional data on the use of macitentan in Eisenmenger syndrome have been obtained, and their publication is awaited (NCT01743001). Blok et al. [35] observed reduction in functional class and improvement in echocardiogram findings, including right ventricle parameters, in patients with CHD-associated PAH whose treatment was switched from bosentan to macitentan; however, there was no difference in the incidence of syncope or heart failure–associated hospitalizations.

Table 2

Studies Evaluating the Effects of Bosentan on Patients with Congenital Heart Disease–Associated Pulmonary Arterial Hypertension.

Study	Patients	6MW	Hemodynamics or functional class change
Galiè et al. [28]	Eisenmenger syndrome	Walk distance change from the baseline of 43.4±8.1 m for treatment vs. −9.7±22.3 m for placebo (P=0.008)	mPAP change from the baseline of −5.0±1.6 mmHg for treatment vs. +0.5±1.4 mmHg for placebo (P=0.0363)
Diller et al. [29]	VSDs, ASDs, PDA, APW, CLs	Baseline 284±144 m, at 1–2 years 408±144 m (P=0.03)	Not reported
Díaz-Caraballo et al. [30]	Eisenmenger syndrome	Baseline 266±161 m, final evaluation, which was the mean of 25-month follow-up distances, 347±133 m (P=0.015)	Baseline average NYHA functional class 3.3±0.7, at final evaluation 2.5±0.9 (P=0.002)
Vis et al. [31]	Various congenital heart diseases	Baseline 417±108 m, at 2.5 years 453 m (SD not given) (P=0.003)	No significant difference although a trend toward higher NYHA class was shown in patients without Down syndrome

ASD, atrial septal defect; APW, aortopulmonary window; CL, complex lesion; mPAP, mean pulmonary artery pressure; 6MW, 6-minute walk; NYHA, New York Heart Association; PDA, patent ductus arteriosus; SD, standard deviation; VSD, ventricular septal defect.

Table 3

SERAPHIN Study Evaluating the Effects of Macitentan on Patients with Congenital Heart Disease–Associated Pulmonary Arterial Hypertension [34].

End point	Macitentan 3 mg vs. placebo (hazard ratio with 97.5% CI)	Macitentan 10 mg vs. placebo (hazard ratio with 97.5% CI)
Event related to PAH or death as the first event	0.70 (0.52–0.96), P=0.01	0.55 (0.32–0.76), P≤0.001
Death due to PAH or hospitalization as the first event	0.67 (0.46–0.97), P=0.01	0.50 (0.34–0.75), P≤0.001

CI, confidence interval; PAH, pulmonary arterial hypertension.

Pharmacotherapy targeted at the prostacyclin pathway includes medications such as epoprostenol, treprostinil, and iloprost, which can be delivered via several routes, including intravenous, subcutaneous, oral, and inhaled routes. The use of intravenous therapy is associated with an increased risk of bloodstream infection and paradoxical embolism, while the subcutaneous and inhaled therapies are associated with injection site pain and frequent dosing, respectively. More recently, an oral form of treprostinil received FDA approval as did an oral prostacyclin receptor agonist, selexipag. Intravenous administration of epoprostenol in CHD-associated PAH has shown beneficial effects on functional class, exercise capacity, and pulmonary hemodynamics (Table 4) [36–38]. In a randomized trial of subcutaneously administered treprostinil versus placebo among 109 (23%) patients with CHD-associated PAH, an increase in exercise capacity, particularly in severely ill, was observed. Patients who walked less than 150 m at the baseline on the 6-minute walk test had an increase of 51±16 m (P=0.002) [39]. Inhaled iloprost has been associated with an increase in exercise capacity in patients with Eisenmenger syndrome; however, no change in pulmonary hemodynamics was observed [40]. In the Prostacyclin Receptor Agonist in Pulmonary Arterial Hypertension Study (GRIPHON) trial, selexipag was associated with a lower incidence of death and PAH-associated complications, including in patients in the CHD-associated PAH subpopulation [41].

Table 4

Studies Evaluating the Effects of Epoprostenol on Patients with Congenital Heart Disease–Associated Pulmonary Arterial Hypertension.

Study	6MW/exercise tolerance	Functional class	Pulmonary hemodynamics
Fernandes et al. [36]	Baseline range <20 to 285 yards, 3 months after treatment range 116–576 yards (P=0.01)	Baseline range III–IV, 3 months after treatment range I–III (P=0.009)	PVR range at baseline 12–74 WU m2, after 3 months of therapy PVR range 12–46 WU m2 (P=0.04)
Rosenzweig et al. [37]	Baseline 408±149 m, after long-term (1-year) therapy 460±99 m (P=0.13)	Baseline 3.2±0.7, after long term (1-year) therapy 2.0±0.9 (P≤0.0001)	mPAP at baseline 77±20 mmHg, after long-term therapy 61±15 mmHg (P≤0.01).CI at baseline 3.5±1.6 L min−1 m−2, after long-term therapy 5.9±2.7 L min−1 m−2 (P≤0.01).PVR at baseline 25±13 WU m2, after long-term therapy 5.9±2.7 WU m2 (P≤0.01)
Thomas et al. [38]	Baseline 3.7±1.0 METs, after 12 months of therapy 5.3±1.0 METs (P=0.046)	No changes noted in functional class	mPAP at baseline 70±11 mmHg, after 12 months of therapy 56±11 mmHg (P≤0.001)

CI, cardiac index; METS, metabolic equivalents mPAP, mean pulmonary artery pressure; 6MW, 6-minute walk; PVR; pulmonary vascular resistance; WU, Wood units.

Upfront combination and sequential combination therapy has been shown to be associated with a survival advantage in patients with PAH [42]. Sildenafil add-on therapy in patients with CHD-associated PAH receiving bosentan monotherapy has been associated with an increase in exercise capacity and improvement in clinical status and hemodynamics [43]. After 6 months of therapy, there was a reduction in World Health Organization functional class (2.1±0.4 vs. 2.9±0.3; P=0.042), an increase in 6-minute walk distance (360±51 m vs. 293±68 m, P=0.005), an improvement in hemodynamics (pulmonary blood flow 3.4±1.0 L/min/m² vs. 3.1±1.2 L/min/m², P=0.002), and a reduction in PVR (19±9 WU/m² vs. 24±16 WU/m², P=0.003). However, Iverson et al. [44] failed to show the same beneficial effects in patients with CHD-associated PAH with Eisenmenger syndrome receiving sildenafil and bosentan combination therapy. The Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension (AMBITION) study concluded that upfront tadalafil and ambrisentan combination therapy was associated with a lower risk of clinical-failure events compared with monotherapy [45]. Patients with CHD-associated PAH composed 2% of the AMBITION study population (n=13). Clinical trials pursuing upfront triple oral therapy are currently under way in patients with PAH, including the Efficacy and Safety of Initial Triple versus Initial Dual Oral Combination Therapy in Patients with Newly Diagnosed Pulmonary Arterial Hypertension (TRITON) trial (NCT02558231). Further studies are under way addressing different combination therapies in PAH patients, including those with CHD-associated PAH.

Treat-to-Close Strategy

The treat-to-close strategy was investigated specifically in patients with ASDs and PAH. Among 22 patients undergoing closure of their ASD, the investigators found that use of PAH-specific therapy before closure for 36% of patients (n=8) resulted in significant symptomatic relief before transcatheter shunt closure without any procedure-related complications or adverse events [46]. Before treatment and closure the group treated with PAH-specific therapies had significantly worse hemodynamics on the basis of a higher mean pulmonary arterial pressure (62±21 mmHg vs. 35±8 mmHg, P≤0.01) and lower PVR (9.6±3.8 WU vs. 41±1.1 WU, P≤0.01). After starting medical therapy, the two groups had similar hemodynamic profiles and were successfully treated with transcatheter closure. This study may indicate that treatment as a bridge to closure may be successful in other types of CHD patients, but further research to evaluate this approach is needed.

Conclusion

In patients with CHD-associated PAH, PAH-specific therapy appears to be an effective method in increasing functional capacity, reducing functional class, and producing more favorable pulmonary vascular hemodynamics. Multiple modalities of therapies appear to be effective in treatment among patients with unrepaired as well as repaired defects in a variety of cardiac abnormalities. Although the data are limited, the growing body of evidence seems to support pharmacotherapy in this heterogeneous patient population as the sole available therapy, and in the future it may prove useful as treatment in preparation for surgical intervention.

Conflict of Interest

The authors declare that they have no conflicts of interest

Author Contributions

All authors contributed to the content and the writing of the article. Hassan Alnuaimat takes full responsibility for the content of the article.

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