Safety and efficacy of bosentan in combination with sildenafil in pulmonary arterial hypertension: The COMPASS-3 study

Introduction: Combination therapy may improve outcomes in patients with severe PAH. However, the appropriate time and functional thresholds to initiate such therapy are ill-defined. Aim and objectives: COMPASS-3 assessed the benefits of a bosentan-based stepped approach using a 6-minute walk distance (6MWD) of 380 meters as the functional threshold. Methods: Treatment-naïve PAH patients with a baseline (BL) 6MWD of 150-360 meters were enrolled. Patients received bosentan for 16 weeks and, based on achievement of a 380 meter 6MWD, continued on monotherapy (125 mg bid) or combination therapy (bosentan 125 mg bid + sildenafil 20 mg tid) for an additional 12 weeks. Results: 100 patients were enrolled (mean age 56 years, mean BMI 29.8 kg/m 2 ). At BL, mean ± SE 6MWD was 273±5.6 meters and 79% of patients were functional class (FC) III. By study end, 31 patients (31%) reached the 380 meter threshold, either at Week 16 (monotherapy, n = 16) or Week 28 (combination, n = 15). 6MWD improvement from BL was 22±7.8 meters at Week 16 and 45±11.1 meters at Week 28. At Week 16, 21/93 patients (22.6%) improved ≥ 1 FC from BL. At Week 28, 85 patients had FC evaluated and 34% improved ≥ 1 FC from BL. Both monotherapy and combination therapy were well tolerated. Most common reported adverse events were peripheral edema, dyspnea, headache, dizziness, anemia, and abnormal liver function tests. Conclusions: This study demonstrates that a bosentan-based stepped approach is safe and efficacious, indicating the potential positive effect of combining the two most commonly used oral PAH therapies, bosentan and sildenafil, on functional ability in severe PAH patients.