PAH Treatment Benefits Extend to Patients With Repaired Congenital Heart Disease

For adults patients with repaired congenital heart disease who are also living with pulmonary arterial hypertension (PAH), medications approved to treat PAH may be as beneficial at reducing morbidity and mortality as they are among the patients who do not have congenital heart disease.

Data demonstrating these clinical treatment conclusions were published in JACC: Advances following a pooled analysis of data from 3 randomized, placebo-controlled studies that investigated what are now currently approved PAH treatments: GRIPHON (NCT01106014), which evaluated selexipag; SERAPHIN (NCT00660179), which evaluated macitentan; and Compass-2 (NCT00303459), which evaluated bosentan and sildenafil vs sildenafil monotherapy.^1-4

The prevalence of PAH in adult patients with congenital heart disease varies, with data from the US showing this to be 5% to 10%,⁵ but increasing⁶ and data from Europe showing 4% to 28%.⁷ However, analysis on the impact of treatment for PAH in the setting of congenital heart disease is limited, according to the authors of the present study.¹ Their primary end point was time to first confirmed morbidity/mortality.

Of the 1982 patients included in this study, 177 (8.9%) patients had congenital heart disease–associated PAH (CHD-PAH). They had to be at least 1 year (GRIPHON and SERAPHIN) or at least 2 years (Compass-2) post heart repair surgery, have PAH confirmed via right heart catheterization, and a 6-minute walking distance (6MWD) result of at least 50 meters (GRIPHON and SERAPHIN) or 150 meters (Compass-2).

Patient Data

Patients in the CHD-PAH group receiving the study drug were younger vs the overall study population (mean [SD] age, 41 [16] vs 48 [15] years), and at baseline, fewer patients had World Health Organization functional class (WHO FC) III disease (39% vs 51%), more patients had WHO FC II disease (60% vs 48%), and the mean 6MWD result was longer, at 379.9 (72.9) vs 362.3 (79.5) meters.

When study investigators looked at death due to PAH or hospitalization due to PAH worsening, the risk reductions were similar: 36% and 31%. | Image Credit: © ibreakstock-stock.adobe.com

The most common repaired CHDs across the 3 studies were atrial septal defect (52.1%), ventricular septal defect (11.7%), and patent ductus arteriosus (4.6%).

Study Results

For morbidity and mortality, fewer patients in the CHD-PAH vs overall the PAH cohort receiving the active drug vs placebo experienced an event, at 17% and 31% vs 31% and 44%. Adjusting for age, sex, and time since diagnosis showed this to be a 50% risk reduction (HR, 0.50; 95% CI, 0.26-0.94) for those with repaired CHD who had PAH and similar to the overall finding among the PAH-alone group (HR, 0.63; 95% CI, 0.53-0.75).

When the investigators also looked at death due to PAH or hospitalization due to PAH worsening, the risk reductions trended similar between the CHD-PAH and overall PAH cohorts: 36% (HR, 0.64; 95% CI, 0.32-1.26) and 31% (HR, 0.69; 95% CI, 0.51-0.92), respectively.

For the secondary end points, under a sensitivity analysis, a similar benefit was seen in 6MWD results from baseline to 6 months in the PAH and CHD-PAH cohorts: 13.4 m (95% CI, 2.1-24.7) and 20.1 m (95% CI, –15.9 to 56.2). When changes in NT-proBNP were evaluated, the ratios of active drug to baseline were 0.76 (95% CI, 0.71-0.81) and 0.92 (95% CI, 0.77-1.10), respectively. And lastly, for worsening of WHO FC, the ORs were 0.84 (95% CI, 0.53-1.33) and 0.99 (95% CI, 0.41-2.37), “indicating no difference,” according to the authors.

Hospitalization rates were similar, as well. For those in the overall PAH group, 20.5% of patients receiving the active drug had a PAH-related hospital stay compared with 17.8% in the CHD-PAH group. Annualized incident rate ratios were close to equal, at 1.39 (95% CI, 1.12-1.71) and 1.38 (95% CI, 0.66-2.88), respectively. Total annualized PAH-related hospital days were 15.2 (28.2) vs 8.9 (10.5).

Conclusions

There was a similar total benefit between the overall PAH and CHD-PAH groups for the primary end point, while the PAH group exhibited statistically significant differences when the secondary end points were considered. However, the magnitude of the treatment effect in the CHD-PAH group was noted to be “generally similar.”

The authors noted, “This pooled analysis using data from indicates that there is an improvement in outcomes with PAH therapy in patients with CHD-PAH and provides important evidence to guide medical management of this growing patient population.”

References

1. Outcomes in patients receiving treatment for pulmonary arterial hypertension associated with repaired congenital heart disease. JACC Adv. 2025;4(3):101626. doi:10.1016/j.jacadv.2025.101626

2. Selexipag (ACT-293987) in pulmonary arterial hypertension (GRIPHON). ClinicalTrials.gov. Updated February 4, 2025. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT01106014

3. Study of macitentan (ACT-064992) on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension (SERAPHIN). ClinicalTrials.gov. Updated September 28, 2015. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT00660179

4. Effects of the combination of bosentan and sildenafil versus sildenafil monotherapy on pulmonary arterial hypertension (PAH) (Compass-2). ClinicalTrials.gov. Updated February 4, 2025. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT00303459

5. Pascall E, Tullok RMR. Pulmonary hypertension in congenital heart disease. Future Cardiol. 2018;14(4):343-353. doi:10.2217/fca-2017-0065

6. Jone PN, Ivy DD, Hauck A, et al. Pulmonary hypertension in congenital heart disease: a scientific statement from the American Heart Association. Circ Heart Fail. 2023;16(7):e00080. doi:10.1161/HHF.0000000000000080

7. D’Alto M, Mahadeva VS. Pulmonary arterial hypertension associated with congenital heart disease. Eur Respir Rev. 2012;21(126):328-337. doi:10.1183/09059180.00004712