Sangeeta Joshi, MD Sangeeta Joshi is a fellow for the Division of Pulmonary and Critical Care Medicine. Center for Pulmonary Vascular Disease, Duke University Medical Center , Victor F Tapson, MD Victor Tapson is the Professor of Medicine and Director, Center for Pulmonary Vascular Disease, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center

Originally printed in:
» US Respiratory Disease 2007 - October 2007

Intravenous Treprostinil and Oral Sildenafil Combination Therapy
Gomberg-Maitland and colleagues²³ reported an open-label pilot study assessing the impact of adding oral sildenafil to subcutaneous treprostinil among a cohort of nine stable PAH patients in modified WHO functional class II–IV. Change in exercise tolerance was the primary end-point. Treprostinil doses ranged from 35 to 90ng/kg/min. At the end of the study period patients demonstrated a statistically significant increase in mean treadmill times (using the Naughton-Balke protocol) from 465±167 seconds at baseline to 656±205 seconds after 12 weeks (42% increase; p=0.049). Predictable prostanoid-type effects, including headache, flushing, and jaw discomfort, were reported. One patient withdrew because of onset of dyspnea and chest pain.²³ Such studies are too small for firm conclusions, but are promising.

Inhaled Iloprost and Oral Sildenafil Combination Therapy
Ghofrani et al.²⁴ reported a very short-term randomized, controlled, openlabel trial in 16 patients with NYHA stage III or stage IV PAH (n=16), chronic thromboembolic PH (n=13), or PH due to aplasia of the left pulmonary artery (n=1). All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose 2.8ug). They were then randomly assigned to receive 12.5mg of oral sildenafil, 50mg of sildenafil, 12.5mg of sildenafil plus inhaled iloprost, or 50mg of sildenafil plus inhaled iloprost. Hemodynamic measurements were monitored up to two hours after the doses. The 50mg dose of sildenafil plus iloprost, followed by 12.5mg of sildenafil plus iloprost, showed maximum reduction of PVR and maximum increase in cardiac index.²⁴ Improvements in symptoms and hemodynamics have also been suggested in small investigational studies with sildenafil in combination with subcutaneous treprostinil²³ and oral beraprost.²⁵

Based on the available evidence, the American College of Chest Physicians (ACCP) recently published an algorithm for various treatment options (see Figure 1).² This algorithm indicates the particular functional class for which these therapies are approved; however, certain regimens—such as bosentan as initial therapy for class IV patients or treprostinil as initial treatment for class II patients—would not be typical approaches; class II patients are nearly always handled with oral regimens and class IV patients with parenteral therapy.

Other Ongoing Trials
Several trials are ongoing that should clarify the role of inhaled and oral prostanoids. The TRIUMPH study is a large, phase III, multinational, randomized, placebo-controlled trial examining the efficacy and safety of inhaled treprostinil as add-on therapy to bosentan or sildenafil. The FREEDOM-C study is a major trial using oral treprostinl in combination with an endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor, while the FREEDOM-M study will compare oral treprostinil with placebo. Since parenteral prostacylins have proved to be effective modes of therapy in very ill patients with PAH, gaining additional insight to the inhaled and oral routes will hopefully prove fruitful. The PACES study, in which patients on IV epoprostenol are randomized to sildenafil or placebo, is ongoing.

Summary
The introduction of prostacyclins has significantly improved therapeutic options and survival in patients with PAH, irrespective of the etiology. These drugs have dramatically changed the face of PAH therapy. Based on quality of evidence, therapeutic benefit, and safety, IV prostanoids remain the medication of choice for PAH patients with advanced disease. In less severely ill functional class II and III patients, the choice should be based on clinical judgment, medication safety profiles, and, if possible, convenience. However, the reluctance of a patient with very advanced PAH to agree to parenteral therapy should be strongly countered. The parenteral and inhaled routes are cumbersome, but proven efficacy outweighs the inconvenience, particularly for parenteral therapy. Combination therapy appears to be the way of the future, and a number of trials are under way. Hopefully, future regimens will become increasingly effective, safe, and convenient.