Hemodynamic Effects of First-Line Bosentan and Sildenafil Combination Therapy for Pulmonary Arterial Hypertension

Abstract

PURPOSE: Sequential combination therapy for pulmonary arterial hypertension (PAH) is standard practice, but data on the safety and efficacy of initial combination therapy in PAH are limited. No studies have evaluated the use of two oral first-line agents that target distinct pathobiologic pathways in PAH. METHODS: We conducted a prospective, single-centre, open label study evaluating first-line combination treatment with bosentan and sildenafil in patients with newly-diagnosed PAH. We compared functional, echocardiographic and hemodynamic measurements at baseline, 4 months and 12 months. RESULTS: Thirteen patients with idiopathic (n=6) or connective tissue disease-related PAH (n=7) were enrolled between November, 2009 and January, 2012, and data from 12 patients were available for analysis. All patients were functional class III at enrollment. Two patients experienced drug related hepatotoxicity. Impressive hemodynamic improvements were observed at 4 months, and improvements persisted and even continued in some patients up to one year. Mean pulmonary artery pressure fell at 4 months (51.1±9 mmHg vs. 43.8±14.5 mmHg, p=0.02) and remained low at 12 months (53.7±9.5 vs 39.5±11.8 mmHg, p=0.04). Cardiac index increased by 50% at 4 months (2.0±0.6 vs 3.0±0.8 L/min/m2, p< 0.01) and 63% at 12 months (1.9±0.6 vs 3.1±0.8 L/min/m2, p<0.01). Pulmonary vascular resistance decreased by 49% at 4 months (14.2±9.1 vs 7.4±4.7 Wood Units, p=0.02) and 55% at 12 months (16.5±11.2 vs 7.5±5.3, p=0.01). The magnitude of the observed hemodynamic improvements was dramatic in comparison to the experience with a bosentan or sildenafil monotherapy strategy. Functional and echocardiographic parameters also improved in concert with the hemodynamics: 6-minute walk distance (6MWD) improved from 274±89.4m to 315±126.3 at 4 months (p=0.11) and to 396.5±109.7 at 12 months (p=0.01), as did tricuspid annular plane systolic excursion (TAPSE) (1.5±0.5 cm vs 1.9±0.3 cm and 2.0±0.3 cm, p<0.01) CONCLUSIONS: First-line oral combination therapy with bosentan and sildenafil was associated with impressive improvements in hemodynamics at 4 months, which persisted at one year.