The purpose of this study is to evaluate the strategy of initiating double oral combination therapy with bosentan and sildenafil at the time of diagnosis of pulmonary arterial hypertension (PAH) in a preliminary way.

Current treatment paradigms for PAH suggest adopting goals of therapy with relatively objective parameters such as 6 minute walk distance to determine when to add a second oral agent (1). This often entails observing deterioration in the patient on a single agent before instituting the second one. This strategy could be problematic, as patients may never recover the function lost due to progressive PAH (2). In addition, given the malignant nature of the clinical course of PAH in many cases and the nature of the underlying proliferative vasculopathy, some have argued that altering this paradigm to resemble that used in cancer chemotherapy may be more appropriate (3). That is, "induction" therapy at diagnosis with multiple agents followed by a maintenance phase of treatment might offer significant benefits to the patient.

This open-label pilot study is the first to investigate the potential efficacy and safety of a first-line combination strategy in consecutive patients with PAH in contrast to the "add-on" strategy for combination therapy. It will serve as the basis on which to consider larger, multicenter investigations of this strategy.

1. Hoeper M, et al. Eur Respir J. 2005 Nov;26(5):858-63.
2. Halpern SD, et al. Proc Am Thorac Soc. 2008 Jul 15;5(5):631-5.
3. Provencher S, et al. Chest. 2005 Dec;128(6 Suppl):622S-628S.

Inclusion Criteria:

• Patients with symptomatic Functional Class III PAH in the following categories: Idiopathic (IPAH), Familial (FPAH), Associated with connective tissue disease, Associated with drugs or toxins
• PAH diagnosed by right heart catheterization, defined as: mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, PVR > 3 mmHg/l/min (Wood units) or > 240 dyn sec cm-5, pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg
• Baseline 6 MWT distance > 150 and < 450 m

Exclusion Criteria:

• Treatment with ERAs other than bosentan;
• Treatment with PDE5 inhibitors other than sildenafil;
• Treatment with any prostanoid;
• PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy; valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization
• Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value;
• Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 50%

Consecutive patients with idiopathic pulmonary arterial hypertension (IPAH) or PAH associated with connective tissue disease that are naive to PAH targeted therapies will be enrolled.