SUMMARY Rationale: Pulmonary arterial hypertension (PAH) can be a rapidly progressive disorder and is associated with a high mortality rate, despite medical intervention. With the availability of effective therapy, early disease detection is an important strategic objective to improve treatment outcomes. Resting echocardiography is currently the recommended screening modality for high-risk population groups. However, it is clear that abnormalities in resting hemodynamics (and symptoms) are late sequelae of the pathobiological processes that begin in the distal pulmonary arteries. Exercise stress may unmask early pulmonary vascular dysfunction, however the definition, clinical significance, and natural history of 'exercise PAH' remain undefined. However, based on clinical experience and literature the prevalence is estimated at ~ 20%.Treatment with endothelin receptor blockers has shown a beneficial influence on the clinical performance in patients with exercise induced PAH due to systemic sclerosis and primary pulmonary hypertension. Whether endothelin receptor blockers decrease pulmonary pressures and improve clinical outcome in patients with exercise induced pulmonary arterial hypertension due to congenital heart disease is unknown.

Objective: Identify congenital heart disease patients with exercise-induced pulmonary arterial hypertension. Analyze changes in pulmonary arterial pressures at peak exercise in patients with exercise induced pulmonary arterial hypertension before and after treatment with bosentan, compared to placebo.

Study design: Randomized placebo controlled trial with a study period of 26 weeks.

Study population: Adult congenital heart disease patients with exercise induced pulmonary arterial hypertension (n=40) from the Academic Medical Centre, Amsterdam.

Intervention: After randomization one group (n=20) receives a 125 mg tablet of Bosentan twice daily for 6 months. The other group (n=20) receives placebo for 6 months.

Main study parameters/endpoints: To determine wether bosentan (endothelin receptor inhibitor) decreases mean pulmonary arterial pressure at peak exercise in adult congenital heart disease patients with exercise induced pulmonary arterial hypertension. Furthermore the change in cardiopulmonary exercise capacity and right ventricular function will be investigated.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All investigations, blood analysis excepted, are non-invasive and free of risk. The burden for the patients mainly consists of the time that is consumed by the investigations, namely: history taking + physical examination (15 min); Quality-of-Life- score (15 min); laboratory tests (electrolytes, creatinine, urea, albumin and neurohormones, troponin T); 12 lead electrocardiogram (10 min); exercise echocardiography (30 min); cardiovascular exercise testing (30 min).

The trial medication has a potential risk of liver damage, which will be monitored regularly by laboratory testing of liver transaminases.

Inclusion Criteria:

• adult (>18 years) and mentally competent

• Open or closed septal defect (ASD I/II, VSD, AVSD)

• Open or closed systemic-to-pulmonary shunt (PDA, PAPVC)

• Negative pregnancy test

• Presence of X-PAH

  • One of the following criteria, at peak exercise.
  • mPAP > 34 mmHg with CO ≤ 10 l/min
  • mPAP > 40 mmHg with CO ≤ 15 l/min
  • mPAP > 45 mmHg with CO ≤ 20 l/min
  • mPAP > 50 mmHg with CO ≤ 30 l/min
  • a PVR (slope pressure/flow plot) of > 3 mmHg/l/min

Exclusion Criteria:

• Incapable of giving informed consent

• Pregnancy or lactation (a pregnancy test is offered to every female patient within fertile age)

• Women of child-bearing age who are sexually active without practising reliable methods of contraception. The use of oral contraceptives only, is not considered reliable. Reliable methods include concomitant use of oral contraceptives and condoms ("Double Dutch"), and those methods with a less than 1% chance of pregnancy during typical use20, including intrauterine contraceptives (Copper T, Mirena), Implanon, and sterilization.

• Substance abuse (alcohol, medicines, drugs)

• Subjects who are not able to perform cardiopulmonary exercise testing

• Any cardiac operation < 6 months before inclusion

• PAH of any aetiology other than the one specified in the inclusion criteria

• Left ventricular ejection fraction < 30%

• Significant impairment of renal function (GFR < 30 ml/min/1.73m2)

• Moderate to severe liver disease: Child Pugh class B or C

• Raised plasma transaminases level > three times upper normal limit

• Arterial hypotension (systolic blood pressure < 85mmHg)

• Anaemia (Hb < 10g/L, or <6.21 mmol/L)

• Significant valvular disease, other than tricuspid or pulmonary regurgitation

• Chronic lung disease or total lung capacity < 80% predicted value

• History of significant pulmonary embolism

• Other relevant diseases (HIV infection, Hep B/C infection)

• Subjects with known intolerance to bosentan or their constituents

• Prohibited medication: any medication listed below which has not been discontinued at least 30 days prior to inclusion

  • Unspecified or other significant medication (glibenclamide or immunosuppression)
  • PAH therapy (endothelin receptor antagonists, PDE-5 inhibitors, prostanoids)
  • Medication which is not compatible with bosentan or interferes with its metabolism (inhibitors or inducers of CYP2C9, CYP3A4) or medication which may interfere with bosentan treatment according to the investigator