Subcutaneous Trepostinil for Pulmonary Hypertension

Two studies comparing subcutaneous trepostinil and placebo were included in a Cochrane review[Abstract] 1. A 12-week multicenter RCT 2 included 470 subjects (mainly NYHA functional class III) with pulmonary arterial hypertension, either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts. The other study 3 was a 8-week pilot study including 23 subjects (mainly NYHA III) with primary pulmonary artery hypertension. The larger study showed that exercise capacity improved with treprostinil and was unchanged with placebo; the between treatment group difference in median six-minute walking distance (6-MWD) was 16 m (p = 0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology. The other study reported no significant difference in mean change from baseline scores between treprostinil and placebo. Effect on NYHA functional class was not reported in either study. There was a significant difference in mean change of pulmonary artery pressure from baseline in favour of treprostinil of -2.71 mmHg (95% CI -4.2, -1.23). However there was considerable statistical heterogeneity between the two studies (I2=57.6%). In the larger study, treprostinil significantly improved indices of dyspnea, and signs and symptoms of pulmonary hypertension. The other study reported non-significant differences in the Borg Dyspnoea Score and Dyspnoea Fatigue Rating.

Infusion site pain was more common with treprostinil compared with placebo (OR 17.32, 95% CI 10.96 to 27.39), as was the likelihood of withdrawing due to drug-related adverse events (OR 13.47, 95% CI 2.57 to 70.48). In the larger study, 85% of patients in treprostonil group had infusion site pain leading to premature discontinuation from the study in 8% of patients. Three patients in the treprostinil group had an episode of gastrointestinal hemorrhage.

An open-label study 4 retrospectively analysed the effects of subcutaneous treprostinil on outcomes in pulmonary artery hypertension (PAH). 860 PAH patients treated with subcutaneous treprostinil (other PAH therapies were added if needed) were followed for up to 4 years.Out of the 860 patients, 492 (57%) discountinued treatment: 199 due to adverse events, 136 died, 117 discontinued due to deterioration, 29 withdrew consent and 11 underwent transplantation. Survival was 87-68% over 1-4 yrs for all 860 patients and 88-70% over 1-4 yrs with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension (IPAH) subset with baseline haemodynamics (n = 332), observed survival rates over 1-4 years were 91-72% compared with predicted survival rates (based on the National Institute of Health formula) of 69-38%.

Comment: The quality of evidence is downgraded by study quality (unclear allocation concealment).

References

• Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev 2005;(2):CD002994 [Review content assessed as up-to-date: 4 July 2006]. [PubMed]
• Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ, Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165(6):800-4. [PubMed]
• McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, Robbins IM, Tapson VF, McGoon MD, Badesch DB, Sigman J, Roscigno R, Blackburn SD, Arneson C, Rubin LJ, Rich S, Treprostinil Study Group. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003;41(2):293-9. [PubMed]
• Barst RJ, Galie N, Naeije R et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J 2006;28(6):1195-203. [PubMed]