In an infant with congenital heart disease‑associated pulmonary arterial hypertension, how should bosentan be dosed and monitored, and what are the contraindications?

Bosentan for Congenital Heart Disease in Infants

Dosing Recommendations

Bosentan should be initiated at 3 mg/kg/day orally in infants with congenital heart disease-associated pulmonary arterial hypertension (PAH), divided into twice-daily dosing. 1

• This dosing regimen has been demonstrated safe and effective in infants as young as 1.5 years of age with CHD-associated PAH 1
• The American Heart Association guidelines support bosentan as first-line oral therapy for lower-risk pediatric PAH patients 2
• A water-soluble, cloverleaf formulation has been approved for use in children with PAH in Europe, facilitating administration in younger patients 3

Monitoring Requirements

Long-term monitoring of liver function tests is mandated with bosentan therapy, typically performed monthly. 3

Hepatic Monitoring

• Elevated hepatic aminotransferase levels occur in approximately 2.7% of children (compared to 11% in adults) 3
• Monthly liver function test monitoring is required throughout treatment duration 3
• The discontinuation rate from bosentan is 14% in children compared with 28% in patients ≥12 years of age 3

Clinical Monitoring Parameters

• Serial echocardiograms should be performed to assess right ventricular function and estimate pulmonary artery pressures 2
• NT-proBNP or BNP levels serve as biomarkers of disease severity 2
• WHO functional class assessment at baseline and follow-up visits 3
• Six-minute walk distance in children >8 years of age 2

Hemodynamic Assessment

• Cardiac catheterization is recommended before initiating therapy to measure pulmonary vascular resistance index (PVRI) and confirm diagnosis 2
• Repeat catheterization should be considered for patients experiencing clinical deterioration or worsening PH by echocardiogram 4

Expected Clinical Outcomes

Bosentan produces sustained clinical and hemodynamic improvement in the short-to-intermediate term, with 2-year survival estimates of 91% in children with CHD-associated PAH. 3

Short-Term Benefits (≤1 year)

• Significant reduction in right ventricular systolic pressure from 96±11 mmHg to 71±26 mmHg 1
• Improvement in WHO functional class from 2.6±0.6 to 1.7±0.6 1
• Reduction in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi) 5
• Improved exercise capacity as measured by 6-minute walk distance 3

Long-Term Considerations

• Beneficial response progressively declines after 1 year, with more rapid decline in children who have more severe disease at baseline 3
• At 4-year follow-up, the Kaplan-Meier estimate of disease progression is 54%, with survival estimate of 82% 3
• After 3 years, bosentan is continued as monotherapy in only 21% of children with idiopathic PAH, but in 69% of repaired CHD cases 6

Contraindications and Precautions

Bosentan is contraindicated in patients with elevated right atrial pressure and low cardiac output, as these conditions predict poor response to endothelin receptor antagonists. 3

Absolute Contraindications

• Pregnancy (teratogenicity) 3
• Severe hepatic impairment 3

Relative Contraindications and Cautions

• Pre-existing elevated hepatic aminotransferases 3
• Concurrent use of oral contraceptive agents (decreased effectiveness) 3
• Anemia (bosentan may worsen) 3

Important Drug Interactions

• Bosentan pharmacokinetics are not altered by concurrent sildenafil therapy, making combination therapy safe 3
• Decreased effectiveness of oral contraceptive agents requires alternative contraception methods 3

Clinical Pitfalls to Avoid

Do not initiate bosentan without first performing cardiac catheterization to confirm PAH diagnosis and exclude other contributing factors such as left ventricular diastolic dysfunction, anatomic shunts, or pulmonary vein stenosis. 3

• Avoid relying solely on echocardiography for diagnosis, as cardiac catheterization provides definitive hemodynamic assessment 2
• Do not continue bosentan monotherapy indefinitely without reassessing clinical response; most children require escalation to combination therapy after 1-3 years 6
• Peripheral edema may indicate negative inotropic effects on the right ventricle rather than simple fluid overload 3
• In postoperative CHD patients, ensure optimal treatment of underlying cardiac and respiratory disease before attributing symptoms solely to PAH 3

Therapy Escalation Strategy

Adopt a progressive treatment escalation strategy where PAH-specific drugs are added sequentially if therapeutic targets are not achieved. 2

Indications for Escalation

• Persistent WHO functional class III-IV symptoms despite initial bosentan therapy 2
• Worsening hemodynamics on serial echocardiograms 2
• Elevated or rising NT-proBNP levels 2
• Declining six-minute walk distance in children >8 years 2

Combination Therapy Options

• Addition of PDE5 inhibitor (sildenafil 0.5-2 mg/kg three times daily) 4
• Combination with prostacyclin analogs for severe disease 2
• Bosentan combined with sildenafil and inhaled iloprost may improve survival in severe PAH 2

Special Considerations for Infants

In infants with CHD-associated PAH, bosentan has been safely used in children as young as 1.5 years with appropriate dose adjustment and monitoring. 1

• Treatment duration in the initial safety study averaged 8.6±5 months without significant adverse events 1
• Clinical status remained stable or improved in all treated infants 1
• The 3 mg/kg/day dosing regimen is appropriate and safe for infants and young children 1