In an infant with congenital heart disease‑associated pulmonary arterial hypertension, how does macicentan compare to bosentan regarding pediatric dosing, safety data, monitoring requirements, and suitability for use?

Macitentan vs Bosentan in Infants with CHD-Associated PAH

Bosentan is the only endothelin receptor antagonist with established pediatric dosing, safety data, and efficacy evidence in children with congenital heart disease-associated pulmonary arterial hypertension, whereas macitenan has no published studies in pediatric patients and should not be used in this population. 1

Pediatric Evidence Base

Bosentan: Established Pediatric Data

Bosentan has robust pediatric evidence including weight-based dosing protocols, safety profiles, and efficacy outcomes specific to children with CHD-associated PAH:

• Dosing regimen is well-established: Children weighing 10-20 kg receive 31.25 mg twice daily; 20-40 kg receive 62.5 mg twice daily; >40 kg receive 125 mg twice daily after a 4-week uptitration period 2
• Pharmacokinetics are similar between pediatric patients and adults, with less than 2-fold variability in exposure across weight groups 2
• A water-soluble cloverleaf formulation has been approved specifically for pediatric use in Europe, facilitating administration in younger children 1

Macitentan: No Pediatric Data

Macitentan has been approved in adults with PAH but has no studies currently reported in children, making it unsuitable for use in infants with CHD-associated PAH 1

Safety and Monitoring Requirements

Bosentan Safety Profile in Children

Bosentan demonstrates superior tolerability in children compared to adults:

• Hepatotoxicity occurs in only 2.7% of children versus 7.8% in patients ≥12 years of age, representing a significantly lower risk 1, 3
• Discontinuation rate is 14% in children versus 28% in patients ≥12 years, reflecting better overall tolerability 1, 3
• Monthly liver function testing is mandatory throughout treatment to detect aminotransferase elevations 1, 4
• Hemoglobin monitoring is required as bosentan may cause mild anemia 1, 4

Drug Interactions

Bosentan pharmacokinetics are not altered by concurrent sildenafil therapy, supporting the safety of combination therapy commonly used in pediatric PAH 1, 5

Bosentan reduces the effectiveness of oral contraceptive agents, though this is less relevant in infant populations 1

Clinical Efficacy in CHD-Associated PAH

Bosentan produces sustained hemodynamic improvement in children with CHD-associated PAH:

• Mean pulmonary artery pressure decreases from 64±3 to 57±3 mm Hg (p=0.005) after treatment 1, 6
• Pulmonary vascular resistance decreases from 20±2 to 15±2 U·m² (p=0.01) 1, 6
• Two-year survival estimates are 91% in children treated with bosentan 1, 6
• WHO functional class improves or remains stable in 90% of patients 1, 6

Important Caveats About Long-Term Efficacy

Therapeutic benefit declines after the first year, with more rapid decline in children who have more severe disease at baseline 1

At 4-year follow-up, disease progression occurs in 54% of patients with a survival estimate of 82%, indicating that bosentan is not curative and many patients require therapy escalation 1

Critical Clinical Pitfalls

Do not use bosentan as a substitute for timely surgical repair in infants with isolated ventricular septal defects and operable hemodynamics (PVRI <6 WU·m² or PVR/SVR <0.3) 7

Early surgical repair before 9 months of age is the definitive therapy for isolated VSD, resulting in normal pulmonary artery pressure at 1 year regardless of preoperative hemodynamics 7

Bosentan may be considered as a bridge to surgery only in infants with PVRI ≥6 WU·m² or PVR/SVR ≥0.3 with poor acute vasodilator response, followed by repeat catheterization after 4-6 months to reassess operability 7

Peripheral edema during therapy may reflect negative inotropic effects on the right ventricle rather than simple fluid overload, requiring careful assessment 1

Monitoring Parameters During Treatment

Serial assessments should include:

• Monthly liver function tests to detect hepatotoxicity 1, 4
• Regular hemoglobin/hematocrit measurements to monitor for anemia 4
• Serial echocardiograms to assess right ventricular function and estimate pulmonary artery pressures 4, 5
• NT-proBNP or BNP levels as biomarkers of disease severity 4
• Repeat cardiac catheterization after 4-6 months when used as a bridge to surgery to reassess PVRI and operability 7

Contraindications

Bosentan is contraindicated in:

• Pregnancy due to teratogenic effects 4, 5
• Severe hepatic impairment 4
• Patients with elevated right atrial pressure and low cardiac output, as these hemodynamic profiles predict poor response to endothelin receptor antagonists 4