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Mahmoud, A.K.; Abbas, M.T.; Kamel, M.A.; Farina, J.M.; Pereyra, M.; Scalia, I.G.; Barry, T.; Chao, C.; Marcotte, F.; Ayoub, C.; et al. Current Management for PAH-CHD. Encyclopedia. Available online: https://encyclopedia.pub/entry/53332 (accessed on 08 July 2024).
Mahmoud AK, Abbas MT, Kamel MA, Farina JM, Pereyra M, Scalia IG, et al. Current Management for PAH-CHD. Encyclopedia. Available at: https://encyclopedia.pub/entry/53332. Accessed July 08, 2024.
Mahmoud, Ahmed K., Mohammed Tiseer Abbas, Moaz A. Kamel, Juan M. Farina, Milagros Pereyra, Isabel G. Scalia, Timothy Barry, Chieh-Ju Chao, Francois Marcotte, Chadi Ayoub, et al. "Current Management for PAH-CHD" Encyclopedia, https://encyclopedia.pub/entry/53332 (accessed July 08, 2024).
Mahmoud, A.K., Abbas, M.T., Kamel, M.A., Farina, J.M., Pereyra, M., Scalia, I.G., Barry, T., Chao, C., Marcotte, F., Ayoub, C., Scott, R.L., Majdalany, D.S., & Arsanjani, R. (2024, January 02). Current Management for PAH-CHD. In Encyclopedia. https://encyclopedia.pub/entry/53332
Mahmoud, Ahmed K., et al. "Current Management for PAH-CHD." Encyclopedia. Web. 02 January, 2024.
Current Management for PAH-CHD
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This entry is adapted from the peer-reviewed paper 10.3390/jpm14010005

Current management of patients with congenital heart disease has increased their survival into adulthood. This is accompanied by potential cardiac complications, including pulmonary hypertension associated with congenital heart disease (PAH-CHD). PAH-CHD constitutes a challenging subgroup of pulmonary hypertension and requires expert management to improve quality of life and prognosis. Novel agents have shown a significant improvement in morbidity and mortality in patients with pulmonary arterial hypertension.

pulmonary hypertension congenital heart disease sildenafil bosentan

1. Eisenmenger Syndrome

1.1. Endothelin-1 Pathway and ENDOTHELIN RECEPTOR ANTAGONISTS

Endothelin-1 (ET-1) is a very potent vasoconstrictor which is mainly released by endothelial cells. It works by binding to two different G-protein subtypes (ET-A, ET-B) in the pulmonary vessels’ smooth muscle cells and induces vasoconstriction and muscle cell proliferation [1].
Bosentan is an oral dual-endothelin-receptor (ET-A, ET-B) antagonist (ERA) which is the most studied ES targeted treatment [2]. The Bosentan Randomized Trial of Endothelin Antagonist THErapy-5 (BREATHE-5) was the first multicenter, double-blind, randomized, placebo-controlled trial studying the benefits of bosentan as a PAH-CHD targeted treatment. In total, 54 patients with ES were included in the study and randomized either to bosentan (37 patients) or placebo (17 patients) for 16 weeks. It demonstrated improved 6 min walk distance (6MWD) by 13% among patients in the bosentan group compared to the placebo group, which decreased by 3%. In addition, there were statistically significant reductions in PVR (9.3% reduction with bosentan vs. 5.4% increase with placebo) and mPAP (decreased by 5 mmHg with treatment vs. 0.5 mm Hg increase with placebo) and improved functional status [3].
An open-label continuation study followed BREATHE-5 and included 37 patients for 40 weeks of therapy; this investigation confirmed and maintained improvements in exercise and functional capacity with longer follow-up [4]. A major side effect included two patients (5.4%) with increases in liver aminotransferases to three times above the upper limit of normal. However, this side effect is dose-dependent and reversible after dose reduction or withdrawal. Accordingly, patients on bosentan should have their liver function monitored monthly [5].
The EARLY study (treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan) was a double-blind, randomized, controlled trial which included 185 patients aged 12 years or older with WHO FC II PAH. Among the included patients, 32 of them had PAH-CHD. At 6 months follow-up, the mean PVR was reduced to 83.2% of the baseline value in the bosentan group and increased to 107.5% of the baseline value in the placebo group (p < 0.001) [6]. An open-label extension phase of this study was performed with a median bosentan treatment of 51 months. It showed that most patients exposed to long-term bosentan maintained or improved their functional class; however, 20% of cases discontinued bosentan treatment due to side effects, which were most commonly elevated liver enzymes, or failure of treatment and worsening of PAH [7].
A small retrospective study reviewed 18 adult patients with PAH-CHD (15 of them with ES) treated with bosentan. No significant increase in liver transaminases was seen, and patients showed both improvements in functional class and 6MWD compared to baseline [8].
Macitentan is the newest studied oral dual-ERA. The Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity (MAESTRO) study included 226 patients with ES and functional class II–III who were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. At baseline, 60% of patients were in WHO functional class II and 27% were receiving phosphodiesterase type-5 inhibitors (PDE-5is). The MAESTRO trial showed that there was no significant improvement in the primary endpoint of 6MWD in patients with ES receiving macitentan [9]. Additionally, no pertinent trends were observed for the secondary endpoints (improvement in WHO functional class). Among exploratory endpoints (NT-proBNP levels and changes in pulmonary vascular resistance index), this treatment decreased NT-proBNP levels and improved the PVR index.
Based on the current data, the AHA/ACC and ESC guidelines recommend bosentan as first-line medical therapy in patients with PAH-CHD who are not eligible for defect closure [10][11]. Of note, both of the newer ERA’s macitentan and ambrisentan are dosed once daily and neither require monthly testing of liver function tests, making them a more favorable alternative to bosentan.

1.2. Phosphodiesterase-5 Inhibitors

PDE-5i therapy targets another pathway by blocking the PDE-5 enzyme which prevents cGMP and cAMP degradation and increases their levels in pulmonary smooth muscle cells, leading to relaxation and vasodilation of the pulmonary vascular bed [12].
Sildenafil and tadalafil are widely used in PAH patients. Their adverse reactions may include vomiting, headache, bronchitis, pyrexia, and diarrhea. In combination with nitrates, they can cause fatal hypotension [13]. In a systematic review of 36 studies with 2,999 participants (all with pulmonary hypertension followed for at least 14 weeks), 11 studies included patients with PAH-CHD. This study showed improvements in WHO functional class and 6MWD in the PDE-5i group versus placebo. Furthermore, the PDE-5i plus combination therapy showed additional improvement in 6MWD [14].
A preliminary observational study investigated 16 symptomatic ES patients for a daily dose of tadalafil during a 12-week follow-up. There was a significant reduction in PVR at 12 weeks (19.22 ± 8.23 to 17.02 ± 6.19 Wood units; p = 0.03). None of the patients had significant adverse effects from the treatment [15].
In a randomized study, 28 patients with ES were given tadalafil or placebo for 6 weeks followed by crossover to the other drug after a washout period of 2 weeks. All patients showed significant improvement in 6MWD (404.18 ± 69.54 m vs. 357.75 ± 73.25 m, p < 0.001), and tadalafil produced a significant decrease in PVR (−7.32 ± 1.58, p < 0.001) and WHO functional class (1.96 ± 0.18 vs. 2.14 ± 0.44, p = 0.025) [16].

1.3. Soluble Guanylate Cyclase Stimulator

Soluble guanylate cyclase (sGC) stimulators are a class of drugs that works directly on the NO pathway; riociguat was the first drug approved in this class and works with dual mechanisms: (1) it enhances the binding between sGC and endogenous NO by stabilizing their bond, and (2) it directly stimulates sGC independently to NO (in contrast to PDE-5is, whose action is dependent on the endogenous NO) [17].
Switching to riociguat versus maintenance therapy with PDE-5is in patients with pulmonary arterial hypertension (REPLACE) was a multicenter, open-label, randomized, controlled trial that included 226 patients who were assigned to riociguat (n = 111) or to the PDE-5i (n = 115). In these groups, 24 and 19 patients had a diagnosis of PAH-CHD, respectively. The primary endpoint (defined as clinical improvement by week 24) was met by 45 (41%) patients in the riociguat group and 23 (20%) in the PDE5i group (OR 2.78, p < 0.001). The most frequently occurring adverse events in the riociguat group were hypotension (14%), headache (13%), and dyspepsia (9%) [18]. This study suggested that switching to riociguat from a PDE-5i could offer therapy escalation in patients with PAH.
Riociguat is dosed at 8 h intervals, making patient compliance more challenging. Also, care must be taken to make sure patients do not take riociguat with PDE-5is simultaneously, or profound hypotension may ensue.

1.4. Prostacyclin Pathway

Prostacyclin is a potent antiplatelet and vasodilator molecule released from the endothelial cells of pulmonary vessels. It acts directly on the surface receptor known as “IP”, triggering the activation of adenylate cyclase enzyme that increases intracellular cAMP. This process results in the prevention of platelet aggregation, the relaxation of smooth muscles, the inhibition of smooth muscle cell proliferation, and the vasodilation of pulmonary vasculature [19][20]. The short half-life of prostacyclin makes its use in the treatment of PAH patients challenging [21].
Epoprostenol, iloprost, and treprostinil are synthetic prostacyclin analogues which can be administered by intravenous (I.V) or subcutaneous (S.C) routes. They could carry systemic side effects, and for the I.V. route, a permanent I.V. catheter needs to be placed, which may be associated with complications such as obstruction and infection [22]. Treprostinil and iloprost can be administered by inhalation, which maximizes the pulmonary therapeutic effects and minimizes the systemic effects [23][24][25].
A clinical trial investigated the role of I.V. epoprostenol in 20 patients with PAH-CHD who failed conventional therapy. The study showed that after one year of use of epoprostenol, mPAP decreased by 21% (p < 0.001), and there were improvements in the cardiac index (3.5 ± 2.0 to 5.9 ± 2.7 L/min/m2, p < 0.001) and PVR (25 ± 13 to 12 ± 7 WU, p < 0.001) [26].
An observational study interpreted the effect of S.C. treprostinil in adult patients with PAH-CHD. In terms of hemodynamics, PVR significantly decreased (18.4 ± 11.1 to 12.6 ± 7.9 WU congenital heart rate, p = 0.003). Clinical symptoms improved after 12 months, with increase in 6MWD by a mean of 114 m (p < 0.001) and a significant improvement in functional class [27].
In a 48-week clinical trial studying the effect of long-term iloprost nebulized treatment in patients with ES, a significant decrease in mPAP and PVR (all p < 0.05) was demonstrated. There was also a significant improvement in functional class (p = 0.006) and 6MWD (310.6 ± 44.7 to 399.7 ± 80.8 m, p < 0.001) [28].
Selexipag is a novel drug in the treatment of PAH which is a direct prostacyclin receptor agonist. A prospective cohort study included 34 adult patients with PAH-CHD, 21 of whom had ES and 11 had PAH after CHD correction. This study confirmed the clinical benefit of selexipag in patients with PAH after defect correction and showed that these patients had more clinical benefit than ES. Additionally, tolerability for selexipag was low in patients with ES [29].
Selexipag use in ES has also been described in case series. In a report of five cases with ES who started selexipag on a background of combination therapy, an improvement in functional class was described [30]. Another case series studied five patients, three of them with ES, revealing a significant improvement in WHO functional class, 6MWD, and an improvement in hemodynamics [31].

1.5. Combination Therapy

The AMBITION trial, a double-blind randomization study that included PAH patients (including PAH-CHD), showed that initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical failure events than monotherapy. Additionally, the OPTIMA trial (a prospective multicenter study enrolling patients with PAH, including PAH-CHD) demonstrated that initial double combination therapy with macitentan and tadalafil showed a significant improvement in cardiopulmonary hemodynamics, functional class, NT-proBNP, and risk profile in newly diagnosed patients, from baseline to week 16. These findings support the early prescription of double oral combination therapy with an ERA and PDE-5i to optimally treat PAH [32].
In a retrospective cohort study including 60 patients with PAH-CHD (32 with ES, 9 with coincidental shunts, 18 with postoperative PAH, and 1 with a significant left-to-right shunt), prostanoids were added to dual combination therapy at maximum doses. Triple therapy demonstrated a significant improvement in 6MWD, WHO functional class, and NT-proBNP levels at 2 years. The addition of prostanoids was especially favorable for patients with pre-tricuspid defects and non-ES [33].

2. PAH Associated with Prevalent Left-to-Right Shunts

Patients with unrepaired, moderate to large, systemic-to-pulmonary shunts and mildly to moderately elevated PVR constitute the second group of PAH-CHD. These patients are in an earlier stage pathophysiologically compared ES but require more complex management strategies due to a lack of evidence and their limited inclusion in clinical trials [34][35]. The decision to close the shunt or to use medical therapy depends on several factors, including the severity of PAH, increased PVR, and the location and size of the defect [36].
Patients with large post-tricuspid shunts (ventricular septal defect [VSD], patent ductus arteriosus [PDA]) usually develop pulmonary vascular disease in early childhood, which makes shunt closure inadvisable [35]. Patients with PAH and pre-tricuspid shunts (atrial septal defect [ASD]), however, are more challenging to manage because of the controversy in guidelines over shunt closure versus PAH-specific therapy [35][37]. This group usually requires additional testing to determine their operability [38][39]. Noninvasive testing such as with echocardiography may be sufficient for some patients, but the majority would benefit from right heart catheterization, which can assess pressures and estimate PVR using the Fick principle [10][38]. The most accurate estimation of PVR requires direct Fick with the measurement of oxygen consumption, but this is not available in most laboratories. Therefore, estimated oxygen consumption is used to calculate cardiac output with the indirect Fick method, which is a major source of bias [10]. This method has been shown to have low accuracy and is no longer recommended by the guidelines [40].
Although there is agreement between guidelines that shunt closure is contraindicated in a subset of patients with severe pulmonary vascular disease, the operability cut-off values for shunt closure vary and are not definitively established [41]. The AHA/ACC guidelines are less conservative in recommending closure, classifying the operability of the second group of PAH-CHD patients into three subgroups based on their baseline hemodynamics and response to acute vasodilator testing [42]. Shunt closure is advised for patients with PVR < 4 WU*m2, Rp/Rs < 0.3 and discouraged for patients with PVR > 8 WU*m2, Rp/Rs > 0.5 as they approach the Eisenmenger physiology [38][42]. The third group with PVR 4–8 WU*m2, Rp/Rs 0.3–0.5 is a “grey” zone that requires a case-by-case approach to weigh the risks and benefits of shunt closure versus targeted PAH therapy with periodic re-evaluation for operability [36][42]. The decision to operate needs expertise that considers the individual clinical characteristics of the patient (age, shunt location, comorbidities) as well as additional parameters such as the degree of reversibility and biventricular systolic and diastolic functions [39]. If more information is needed, a decrease in CO and/or an increase in RV (right ventricle) filling pressures on the balloon occlusion test would indicate against defect closure [36].
The ESC guidelines use more restrictive criteria for shunt closure with lower PVR thresholds [41]. The ESC also contraindicates closure for patients with exertional hypoxemia and recommends fenestrated closure only for ASD patients with moderate to severe PAH who respond to targeted therapy, while the AHA/ACC does not explicitly mention these options [10][41]. It is very important to identify patients who will normalize their hemodynamics after shunt closure as the persistence of PAH after shunt closure carries a poorer prognosis compared to other groups of PAH-CHD [37][43].
In inoperable patients, the optimal risk–benefit ratio of different treatment strategies depends on the timing and purpose of vasodilator therapy. An expectant strategy waits for the shunt to clearly reverse to right to left before using pulmonary vasodilators in an attempt to delay or avoid the long-term risk of heart failure and death associated with these drugs [44][45]. “Treat and repair”, “intent to repair”, and “treat to close” are different terms that describe similar strategies that include lowering the PVR first with pulmonary vasodilator therapy as a bridge to close the shunt, either by surgery or a device. Although these strategies may offer a cure for some patients, they are risky and require careful selection of patients and close monitoring of PVR. In addition, they lack the support of long-term data, and more research is needed to investigate their outcomes and risks [35][38][46][47].

3. PAH Associated with Small/Coincidental Defects

This group consists of patients with a small/coincidental defect (usually VSD < 1 cm or ASD < 2 cm) that is not considered to be the cause of PAH. They have a similar profile to idiopathic PAH, and closure of the defect is contraindicated as in ES [38]. The main treatment strategy is proactive disease targeting therapy (DTT). Lung or heart–lung transplantation may be considered if symptoms do not improve with optimal oral and intravenous therapy [48]. The EARLY study of bosentan by Galie et al. included a small number of patients with small/coincidental defects and there was a significant reduction in PVR in the overall population [6][49]. However, further studies with larger sample size are needed to better assess the efficacy of these drugs in this specific subgroup.

4. Postoperative PAH

This group comprises patients who develop or experience persistence or recurrence of PAH after defect closure. The clinical phenotype is often aggressive and has a poor prognosis, so prevention of this scenario is crucial [37][50]. Late diagnosis and closure are the most likely causes of this, but genetic predisposition may also play a role, especially when PAH occurs many years after defect correction [38]. Like the previous group, these patients resemble idiopathic PAH patients and need close monitoring and proactive DTT, with transplantation as a last resort [51]. For these two groups, upfront combination therapy (ERA and PDE-5i) is recommended for low/intermediate risk patients, and triple therapy (ERA, PDE-5i, and prostanoid) for high-risk patients [10][38]. Anticoagulants may also be indicated due to the prothrombotic nature of idiopathic PAH, which they resemble mechanistically [52].
There is some evidence regarding medical treatment for this subgroup of patients. The randomized, controlled GRIPHON study included 1156 patients with PAH to receive placebo or selexipag in individualized doses. Among the included cohort, 110 patients with corrected PAH-CHD were enrolled. Morbidity events included disease progression or worsening of PAH that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or need for lung transplantation or balloon atrial septostomy. The results showed that selexipag may delay disease progression and be well tolerated in patients with PAH, including corrected PAH-CHD [53].
The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a phase 3, double-blind study which included 443 patients with symptomatic PAH to receive riociguat or placebo for 12 weeks. It included 35 patients with postoperative PAH-CHD. There was significant improvement in 6MWD in the riociguat group. In addition, there were significant improvements in PVR, NT-proBNP levels, WHO functional class, time to clinical worsening, and Borg dyspnea score. The most common serious adverse event was syncope [54].

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Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ahmed K. Mahmoud
,
Mohammed Tiseer Abbas
,
Moaz A. Kamel
,
Juan M. Farina
,
Milagros Pereyra
,
Isabel G. Scalia
,
Timothy Barry
,
Chieh-Ju Chao
,
Francois Marcotte
,
Chadi Ayoub
,
Robert L. Scott
,
David S. Majdalany
,
Reza Arsanjani
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Revisions: 2 times (View History)
Update Date: 03 Jan 2024
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