Pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) is one of the most common types of PAH [1–3]. Recent progress in medical and surgical treatment of CHD means that nowadays most affected patients survive into adulthood [4], leading to an increase in the prevalence of PAH-CHD. The prevalence of PAH among adult patients with CHD is estimated to be 5–10%, depending on the underlying shunt size and location and complexity of the CHD [5]. PAH-CHD stratified by shunt lesions consists of heterogeneous subgroups [6,7], as follows: (1) Eisenmenger syndrome, (2) PAH associated with predominant systemic-to-pulmonary shunts (either correctable or not), (3) PAH with small/coincidental defects, and (4) PAH after repair (corrected PAH-CHD). Treatment of PAH-CHD requires a delicate and meticulous approach by PAH-CHD experts, including precise early diagnosis of CHD and confirmation of PAH-CHD, including operability, based on the results of pulmonary vascular resistance and vasoreactive tests. Timely corrective surgery or intervention is imperative in operable PAH-CHD, and staged palliation for further definitive treatment is crucial in the treatment of complex or borderline PAH-CHD. Targeted PAH therapy and suitable supportive care, including diuretics, oxygen supplementation, and the use of appropriate anti-coagulation agents are important at every strategic point in-patient care [7]. Recent guidelines recommend sequential or upfront use of a combination of selective PAH drugs, targeting endothelin, nitric oxide, and prostacyclin pathways [8]. Selexipag (Uptravi, Actelion Pharmaceuticals) is a highly selective, oral, long-acting prostacyclin receptor (IP receptor) agonist [9,10]. It was approved by the Food and Drug Administration in December 2015 and by the European Medicines Agency in May 2016, allowing for marketing of an oral combination therapy, targeting the prostacyclin pathway. A phase III trial (GRIPHON) has shown that, compared to placebo, selexipag reduced the risk of mortality or major complications associated with PAH [11] and improved the results of a 6-minute walking distance test. Thereafter, many studies have demonstrated the clinical efficacy and tolerability in various patient groups, including patients with connective tissue disease [12,13], chronic pulmonary thromboembolism [14], as well as pediatric populations [15]; heterogeneous real-life data also appear to support the clinical trial findings [16]. Regarding treatment of PAH-CHD, post-hoc analysis of the GRIPHON study data has demonstrated that selexipag may delay disease progression and is well-tolerated [17]; however, this trial only included corrected PAH-CHD patients. Thus, the clinical efficacy and safety of selexipag among patients with PAH-CHD requires elucidation. This study examined the efficacy and safety of selexipag in PAH-CHD patients, including patients with Eisenmenger syndrome and partially repaired CHD.

Adult patients (age >18 years), prescribed selexipag, from December 2017 to August 2019 at the Division of Pediatric Cardiology, Congenital Heart Center, Severance Cardiovascular Hospital, a tertiary university hospital, were retrospectively screened and enrolled in this study. Patients with PAH-CHD, previously confirmed by right heart catheterization, were included; patients with idiopathic PAH was excluded. At baseline, all patients were treated with all types of PAH drugs, except prostanoids; selexipag was added to the baseline PAH-targeting drug.

The Institutional Review Board of Severance Hospital (4-2019-1083) approved the study protocol, and this study was performed in accordance with the Declaration of Helsinki; the requirement for acquisition of informed consent was waived owing to the study’s retrospective nature.

Although this study was performed retrospectively, our clinical policy strictly followed the relevant PAH management guidelines [8]. Right heart catheterization was performed using a Berman or Swan-Ganz catheter, and cardiac output was measured by thermodilution. The pulmonary vasoreactivity test was performed using inhaled O₂ and iloprost. According to the guidelines on the pulmonary vascular resistance index, the values >8 Wood unit (WU)*m² were indicative of inoperable cases [8,18]. In patients with borderline PAH (pulmonary vascular resistance index range, 4–8 WU*m²) with an atrial septal defect (ASD), treatment modalities (surgery vs. interventions, and approaches with vs. without fenestration) were discussed and decided on in a multidisciplinary team meeting. When indicated, transcatheter closure of the atrial septal defect was performed, as previously reported. [19,20] Temporary balloon occlusion test was performed for additional information of reversibility of PAH as well as testing for masked left ventricular restriction in patients with ASD.

Except for patients with an atrial septal defect, all patients with CHD had Eisenmenger syndrome. ASD patients with acceptable range of PAH were treated either completely repaired (N = 1) or partially repaired with fenestration (N = 5). However, one patient with uncorrectable PAH was not repaired, and has been treated with PAH drugs and will be analyzed by further catheterization, which is so called “PAH treat and repair strategy” [21]. Selexipag treatment was initiated at a dose of 200 µg twice daily which was increased weekly or biweekly in increments of 200 µg twice daily until unmanageable side effects developed. When unmanageable side effects developed, the dose was decreased by 200 µg twice daily. Up-titration was resumed once side effects had subsided or become tolerable; nevertheless, increases were administered at a slower rate. If intolerable and untreatable side effects recurred, the dose was decreased by 200 µg once or twice daily, and the adjusted dose was regarded as the maintenance dose. We prescribed supportive analgesics (ibuprofen) in all cases as well as antiemetic (metoclopramide) and antidiarrheal drugs (loperamide), as required. All supportive drugs were prescribed at their usual dosage and increased to the maximal dosage, as required and indicated.

Baseline characteristics, hemodynamic and echocardiographic data, World Health Organization functional class, 6-minute walking distance test results, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were assessed. Data from the last available right heart catheterization measurement were adopted as the baseline. Patients were followed up every 1–4 weeks during selexipag dose titration and every 3–6 months thereafter. Side effects of selexipag and World Health Organization functional class were assessed at every clinic visit by the attending physician. The 6-minute walking distance test was performed according to the American Thoracic Society guidelines [22]. Transthoracic echocardiography was performed in supine and left lateral decubitus positions; the basic 2-dimensional and M-mode echocardiography, and continuous wave and tissue Doppler data were obtained. Data on echocardiographic prognostic markers of PAH such as the pressure gradient of tricuspid regurgitation, tricuspid annular plane systolic excursion of the right atrial area, and presence of pericardial effusion were collected. The doppler image of tricuspid regurgitation was obtained well before and after selexipag treatment in all patients, which might be related with patient characteristics who had severe PAH and at least mild tricuspid regurgitation.

Risk assessment was based on non-invasive methods, as defined in the French registry, and involved the following parameters: Low risk was defined as World Health Organization functional class I–II, 6-minute walking distance >440 m, and NT-proBNP <300 ng/L [23,24].

A total of 14 patients were treated with selexipag at our department; a single patient with idiopathic PAH was excluded from this study. The baseline characteristics of the enrolled patients are summarized in (Tab. 1). Patients were either World Health Organization functional class II (38.5%) or III (61.5%). All patients were already being treated with PAH drugs; 12 patients were receiving monotherapy, (with an endothelin receptor antagonist and a phosphodiesterase type 5 inhibitor prescribed to 9 and 3 patients, respectively) and 1 was on dual therapy. The median treatment duration was 49 months (range, 3–120 months). There were no differences in sex, age, World Health Organization functional class, or baseline PAH drug use between patients with and without Eisenmenger syndrome (data not shown). No patients died during the study period or were lost to follow-up.

In the present study, no patient reached the maximal maintenance dosage of selexipag (mean, 1166 µg/day), as the majority of patients (92.3%) experienced more than 1 side effect. The maximal maintenance dosage was low (<1000 µg/day) in 41.6% of patients, medium (1000–2000 µg/day) in 50% of patients, and high (>2000 µg/day) in one (8.4%) (Fig. 1a). After adjustment for weight, half of the patients reached a dosage of 20–60 µg/kg/day (Fig. 1b).

In the present study, the most common side effect was musculoskeletal pain, followed by headache, and nausea and diarrhea (Fig. 2). No unexpected side effects were reported. One patient with a ventricular septal defect and Eisenmenger syndrome suffered due to intolerable myalgia, resulting in drug discontinuation and exclusion from the present study’s analysis of efficacy and risk reassessment. One patient, who was previously diagnosed with rheumatic arthritis and had suffered from arthralgia prior to selexipag initiation, could not bear the dosage titration, resulting in a maintenance dosage of 400 µg/day.

Following exclusion of one patient due to selexipag discontinuation, 12 patients in total were included in the efficacy analysis. Follow-up (FU) assessment was performed at 12.3 ± 2.8 months after selexipag initiation. After selexipag treatment, the results of the 6-minute walking distance test increased (from 299.2 ± 56.2 m to 363.8 ± 86.5 m, p = 0.039; Fig. 3a) and the tricuspid regurgitation pressure gradient decreased (from 84.7 ± 20.5 mmHg to 61.6 ± 24.0 mmHg, p = 0.018; Fig. 3b). Concurrently, NT-proBNP levels decreased (from 1580 ± 497 pg/mL to 629 ± 220 pg/mL, p = 0.096; Fig. 3c); however, this change was not statistically significant. Furthermore, World Health Organization functional class improved in 5 patients and remained stable in 7 patients. The tricuspid annular plane systolic excursion and right atrium fractional area change showed no relevant changes.

Changes in the risk assessment, based on the French registry group [23], between baseline and follow-up are presented in Fig. 4. Among individual patients, 8 (66.7%) showed improvement, 3 (25.0%) showed no change, and 1 (16.7%) showed worsening at the time of risk reassessment. Individual profiles of risk assessment before and after selexipag was described in (Tab. 2). Among 5 patients with Eisenmenger syndrome, 2 showed improvement in 6-minute walking distance scores (n = 1) and NT-proBNP levels (n = 1), whereas the remaining 3 exhibited no change. As for patients without Eisenmenger syndrome, improvement was observed in 6 cases, and a single patient experienced worsening.

Compared to the low dosage group (n = 5), the medium-to-high maintenance dosage group (n = 7) showed a significant change in 6-minute walking distance scores (88.3 ± 26.4 m vs. 55.3 ± 27.6 m, p = 0.043, Fig. 5a) and tricuspid regurgitation pressure gradient (−33.7 ± 10.9 mmHg vs. −12.5 ± 12.0 mmHg, p = 0.015, Fig. 5b). Concurrently, there was no difference in the change in NT-proBNP levels between the groups (Fig. 5c). Nevertheless, the maintenance dosage did not seem to affect the patients’ PAH status, irrespective of the presence of Eisenmenger syndrome (1371 ± 558 in non-Eisenmenger vs. 880 ± 334 in Eisenmenger, p = 0.112).

The present study reported real-life outcomes of selexipag treatment among PAH-CHD patients, including patients with Eisenmenger syndrome and partially repaired CHD. Previous studies have reported on the successful initiation of selexipag and functional improvement in 4 patients with Eisenmenger syndrome [25] and complex CHD [15]. In the present study, we have included the assessment of selexipag efficacy at improving or at least stabilizing the status of patients with Eisenmenger syndrome or partially repaired CHD.

In the present study, all patients were alive at the end of the study period, and no life-threatening adverse effects were observed. Side effects observed in the present study were consistent with previous reports [11,16]. As in the previous studies, in the present study, the majority of patients experienced side effects.

The maintenance dose in the present study was lower than that reported in previous studies [11,16]. A separate study involving Japanese patients has reported a relatively lower maintenance dose [26]. These discrepancies in dosage might be related to several factors: (1) There is a lack of specialist nursing care to encourage uptake of this treatment among patients; (2) The cost-benefit ratio, particularly among patients with long-term severe PAH, is inadequate, and the concurrent use of selexipag results in marked relief from PAH symptoms even at a low dose required to control side effects; and (3) The optimal dosage for underweight patients or patients who belong to other ethnic groups requires further research.

The present study has shown a marked improvement in the 6-minute walking distance test and a reduction in tricuspid regurgitation pressure gradient despite a relatively lower maintenance dosage. This finding might be accounted for by the study sample characteristics. Other studies have performed dose escalation even in low-risk groups, when the patients could not fulfill the low risk criteria [14]. In the present study, we tended to add selexipag to the regimen of patients with extreme PAH, as sequential add-on therapy is approved by the Korean National Health Insurance Review and Assessment Service for cases involving clinical and/or hemodynamic worsening of PAH but not in cases that do not achieve an improvement in clinical or hemodynamic status during risk assessment (Tab. 3). Low baseline 6-minute walking distance scores and high NT-proBNP levels in this study reflect the clinical status of our patients, as a recent study has shown that a high NT-proBNP level is associated with poor clinical outcomes among PAH patients [27].

A recent post-hoc analysis of the GRIPHON study data has shown the relationship between risk profile and mortality/morbidity among PAH patients [24], demonstrating the benefits of selexipag at improving risk profile even among patients with corrected CHD. The present study adds to the body of clinical evidence, showing the impact of selexipag on improving risk profiles even among patients with Eisenmenger syndrome or partially repaired CHD.

Dose-related efficacy was not evident in the previous real-life study on selexipag; however, it was detected in the present study despite a small number of patients. Nevertheless, this phenomenon should be further investigated in a larger cohort.

This study was a non-randomized retrospective study with some inherent limitations. Moreover, follow-up right heart catheterization data were only available for 3 patients due to the relative shortness of the follow-up period and invasiveness of the test, resulting in right heart catheterization data being excluded from the analysis in the present study. The cardiopulmonary exercise test was performed in selective cases and not included in the present report. Reported clinical improvement might be exaggerated by a combination of a small number of included patients and biases associated with the treatment of high-risk patients. Nevertheless, the clinical efficacy of selexipag as add-on therapy in the present group of high-risk patients is evident as the included high-risk group had severe PAH-CHD despite long-term treatment with PAH drug(s) prior to study enrollment.

The present study contributes to the evidence on the clinical efficacy of selexipag as add-on therapy in the real-life treatment of patients with PAH-CHD, including Eisenmenger syndrome and partially repaired CHD.