PURPOSE: Combination therapy may improve outcomes in patients with severe pulmonary arterial hypertension (PAH). However, the appropriate time and functional thresholds to initiate such an approach are ill-defined. COMPASS-3 assessed the benefits of a bosentan-based stepped approach utilizing a 6-minute walk distance (6MWD) threshold of 380m as the functional threshold.
METHODS: Treatment-naive PAH patients with a baseline (BL) 6MWD of 150-360m were enrolled. Patients received bosentan for 16 weeks and, based on an achievement of a 6MWD of 380m, continued on either monotherapy (125mg bid) or combination therapy (bosentan 125mg bid+sildenafil 20mg tid) for an additional 12 weeks.
RESULTS: 100 patients were enrolled, mean age was 56 years and mean BMI was 29.8 kg/m2. At BL, mean 6MWD was 273.0m and majority of patients were functional class (FC) III (79%). By the end of the trial, 31 patients (31%) had reached the predefined threshold of 380m, either at Week 16 (monotherapy, n=16) or at Week 28 (combination, n=15). Mean improvement in 6MWD from BL was 22m and 45m at Week 16 and 28, respectively. At Week 16, 21/93 (22.6%) of patients had at least 1 FC improvement from baseline. At Week 28, 85 patients had a FC evaluation and 34% had at least 1 FC improvement from baseline. Both bosentan monotherapy and combination therapy with sildenafil were well tolerated. Most common reported adverse events were peripheral edema, dyspnea, headache, dizziness, anemia, and abnormal liver function tests.
CONCLUSION: Results of this study demonstrate that a bosentan-based stepped approach is safe and efficacious.
CLINICAL IMPLICATIONS: COMPASS-3 is one of the first trials to assess the efficacy and safety of combining PAH oral therapies utilizing different and complementary mechanisms of action. The study results demonstrated the potential positive effect of combining the two most commonly used oral PAH therapies bosentan and sildenafil on improving functional ability in severe PAH patients.
DISCLOSURE: Raymond Benza, Grant monies (from industry related sources) Francisco Soto: Research grant-Pfizer.Srinivas Murali: Research support-Actelion, Gilead.; Employee Noam Frey: Employee of Actelion Pharmaceuticals US.; Consultant fee, speaker bureau, advisory committee, etc. Francisco Soto: Advisory board/consultant-Actelion.Fernando Torres: Speaker, Scientific Advisory Board-Actelion; Speaker-Pfizer. Himanshu Gupta: Consultant-Actelion. Myung Park: Advisory board/consultant-Actelion, Gilead, United Therapeutics. Srinivas Murali: Consultant and speaker’ s bureau-Actelion, Gilead. Raymond Benza: Honoraria-Actelion, Encysive, Pfizer.; No Product/Research Disclosure Information