Improved low-risk criteria scores for combination therapy of sildenafil and generic bosentan in patients with congenital heart disease with severe pulmonary hypertension: A prospective open label study

Abstract

Objective We evaluated the efficacy and safety of the bosentan as a sequential add-on therapy with sildenafil in pulmonary arterial hypertension with congenital heart disease (PAH-CHD) patients. Material and method Twenty patients who were receiving sildenafil were given generic bosentan for up to a year. Hemodynamic data was collected from cardiac catheterization at pretreatment and at three months. Comparisons were made between the total scores of the four, low-risk criteria adapted from the 2015 ESC/ERS pulmonary hypertension guidelines, which are: 1) WHO functional class of I or II, 2) 6MWD of more than 440 m, 3) right atrial pressure of less than 8 mm Hg, and 4) cardiac index ≥2.5 L/min/m2, performed at the beginning of therapy, 3-months, 6-months, and 1 year. Results Patients’ average age was 27 ± 11 years old (12–53). PVRi decreased from 16.7 ± 9.5 to 12.7 ± 10.3 Wood unit (WU) m2 (p = 0.025) and PVRi/SVRi decreased from 0.69 ± 0.33 to 0.49 ± 0.32 (p = 0.001). During the follow-up, the composite scoring of the low risk scores for 19 patients was increased significantly from 1.8 ± 1.0 at baseline to 2.3 ± 0.9 at 3 months, to 2.9 ± 0.8 at 6 months, and 3 ± 0.7 at 1 year (p = 0.001). Conclusion We demonstrated intermediate term benefits for generic bosentan as an add-on therapy to sildenafil in patients with PAH-CHD by improving PVRi, and PVRi/SVRi at three months. A significant improvement was also seen in the combined scores of the low-risk criteria from below 2 to 3 at one year (p = 0.001). Thai Clinical Trials Registry (TCTR): TCTR identification number is TCTR20200506006.

Medical treatment of pulmonary hypertension in adults with congenital heart disease: updated and extended results from the International COMPERA-CHD Registry

“…Nearly all other PH registries in Europe and the United States that also include CHD comprise all types of group 1 patients (PAH) but differentiate less precisely between clinical subtypes, treatment characteristics, and outcomes of distinct patient groups (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

“…The reluctance to using combination therapies in PAH-CHD may originate from the fact that, particularly in Eisenmenger syndrome, evidence-based and consensusdriven treatment algorithms are not available, and there is no robust evidence to support the use of PAH combination therapy (23). However, in recent years, some study data and reports have suggested that adults with CHD may also benefit from targeted combination therapy (7,(24)(25)(26)(27)(28). Accordingly, a more aggressive approach is also reflected in the COMPERA-CHD data, as the percentage of initially monotherapy (41%) versus combination therapy (53%) shifted during the observation period in favor of combination therapy.…”

Congenital Heart Disease: The State-of-the-Art on Its Pharmacological Therapeutics

“…Studies have shown that drugs, such as angiotensin receptor blockers [ 124 ]; prostaglandins [ 11 ]; and ACE [ 13 , 14 ], endothelin-1 [ 99 ], and PDE-5 inhibitors [ 12 ], have a positive impact on mortality and quality of life in patients with CHD. Likewise, treatments, such as riociguat [ 120 ], macitentan [ 98 ], and a combination of bosentan with sildenafil [ 94 ], have given positive results, but studies in pediatric patients are needed.…”

“…Studies have shown that the exposure plateau for bosentan is reached at a dose of 2 mg/kg twice daily, making the adequate dose up to 4 mg/kg [ 97 ]. Currently, incremental treatment with bosentan along with sildenafil has been shown to improve pulmonary and systemic vascular resistance in a study with patients ranging from 12 to 53 years with CHD and pulmonary arterial hypertension [ 98 ]. However, macitentan, an analogous-to-bosentan pulmonary vasodilator ERA [ 94 ], improved mortality and morbidity in a placebo-controlled trial of bosentan [ 99 ].…”

“…In a study by Durongpisitkul et al, pulmonary arterial hypertension derived from CHD has shown intermediate-term benefits after the treatment of generic bosentan as a complementary therapy to sildenafil, with a significant improvement in the scores of low-risk criteria after one year [ 98 ]. Additionally, a study by McLaughlin et al assessing the safety and clinical outcomes after the treatment with macitentan in this same CHD population indicated an important number of patients (4268) in follow-up [ 177 ].…”