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

Treprostinil
This synthetic prostacyclin analog is approved for the treatment of PAH in patients with New York Heart Association (NYHA) class II, III, or IV symptoms as a continuous subcutaneous or IV infusion, with the IV route utilized when subcutaneous infusions are not tolerated. Intolerance of subcutaneous delivery is common. As with epoprostenol therapy, treprostinil is most commonly used in patients with advanced class III or IV symptoms together with hemodynamics and a 6MWT distance that parallel these symptoms

Treprostinil has a more favorable administration profile than epoprostenol. The subcutaneous delivery system utilizes a smaller pump and is less cumbersome than a central venous line access; associated complications such as sepsis, thrombosis, and the risk of a major delivery disruption are thus avoided. Unfortunately, local infusion-site pain is quite common and may be intolerable in a substantial proportion of patients, even with supportive management. IV treprostinil compares favorably with epoprostenol as it is stable at room temperature (alleviating the need for ice-packs) and has a longer half-life, which increases safety in the event of delivery system malfunctions. The 48-hour infusion interval allows for medication preparation and cassette changing every other day. The target dose of IV treprostinil is at least twice that of epoprostenol—i.e. usually at least 80ng/kg/min. Drug initiation and teaching protocols are similar to those for epoprostenol.

While treprostinil has been used in patients with advanced PAH, many experts feel that the ‘sickest’ PAH patients, i.e. those with unfavorable hemodynamics and a rapidly progressive symptom complex, merit IV epoprostenol based on a proven mortality benefit.⁴ In addition, there could be an increased rate of Gram-negative bloodstream infections among patients with PAH treated with IV treprostinil compared with epoprostenol.⁸ The latter data, however, were not collected in a controlled manner, so this possibility has not been verified.

Clinical Trials
Simonneau and colleagues⁹ reported a 12-week, double-blind, placebocontrolled multicenter trial comparing subcutaneous treprostinil with conventional therapy in 470 patients with functional class II, III, or IV PAH. These patients had PAH that was idiopathic, associated with connective tissue disease, or with congenital systemic-to-pulmonary shunts. Improved exercise capacity as measured by the 6MWT distance was demonstrated by a median between-treatment-group difference of 16m (p=0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related, but was independent of disease etiology. Concomitantly, treprostinil significantly improved indices of dyspnea, symptoms and signs of PH, and hemodynamics.⁹

Tapson and associates¹⁰ investigated the safety and efficacy of continuous IV treprostinil in patients with PAH in a 12-week, prospective, open-label, uncontrolled, multicenter trial in 16 functional class III or IV IPAH patients, or those with PAH related to connective tissue disease or congenital heart disease. 6MWT distance (mean ± standard error, SE) increased by 82m from baseline (319±22m) to week 12 (400±26m; n=14; p=0.001). There were also significant improvements in the secondary end-points of Naughton-Balke treadmill time (p=0.007), Borg dyspnea score (p=0.008), and hemodynamics (mPAP: p=0.03; cardiac index: p=0.002; pulmonary vascular resistance (PVR): p=0.001) at week 12 compared with baseline. These results are very optimistic, but it should be emphasized that this was not a randomized study. One death, which was unrelated to the study drug, occurred during the 12-week study in a patient who received three days of IV treprostinil and died two weeks later.¹⁰ In a similar open-label trial, Gomberg-Maitland et al.¹¹ transitioned 31 functional class II and III PAH patients from IV epoprostenol to IV treprostinil. Twenty-seven patients completed the 12-week study, and four patients were transitioned back to epoprostenol. Exercise endurance as measured by the 6MWT distance was maintained among the patients completing the transition (438±16m at baseline and 439±16m at week 12, ± standard deviation, SD). At week 12, there was a modest increase in mPAP of 4±1mmHg (p<0.01) and a reduction in cardiac index of 0.4±0.1l/min/m2 (p=0.01). Notably, the dose of IV treprostinil at the end of 12 weeks was more than twice the dose of IV epoprostenol at the start of the study: 83 versus 40ng/kg/min.¹¹

In 2004, the FDA approved the use of IV treprostinil in NYHA functional class II, III, and IV PAH patients in whom subcutaneous infusion is not tolerated. Barst and associates¹² reported the effects of subcutaneous treprostinil followed by the addition of other therapies if needed in 860 PAH patients for up to four years. Of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117 (14%) discontinued due to deterioration, 29 (3%) withdrew consent, and 11 (1%) underwent transplantation. In total, 97 patients (11%) switched from treprostinil to an alternative prostacyclin analog. Bosentan was added in 105 patients (12%) and sildenafil in 25 (3%). Survival was 87% at one year and 68% at four years for all 860 patients, and nearly identical for patients on subcutaneous treprostinil monotherapy. For the IPAH subset with baseline hemodynamics (n=332), survival was 91% at one year and 72% at four years. In contrast, predicted survival for IPAH using the NIH formula was 69 and 38% for years one and four, respectively. The rate of adverse effects was 23%, with 94% of these being pain at the infusion site.¹²