Chest
Volume 126, Issue 2, August 2004, Pages 420-427
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Clinical Investigations
DIFFUSE DISEASES
Treprostinil, a Prostacyclin Analogue, in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease

https://doi.org/10.1378/chest.126.2.420Get rights and content

Study objectives:

To assess the efficacy and safety of continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD).

Design:

Two multicenter, randomized, double-blind, placebo-controlled, prospective trials of treprostinil vs placebo in 470 patients with PAH.

Patients:

A subset of 90 patients with PAH and CTD, including systemic lupus erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap syndrome.

Interventions:

Patients received either treprostinil (initiated at 1.25 ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion. The maximum dose of treprostinil allowed was 22.5 ng/kg/min.

Measurements:

Six-minute walk (6MW) distance and dyspnea-fatigue scores were determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were obtained at baseline and at 12 weeks.

Results:

At baseline, most patients had New York Heart Association class III symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5 ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2 ± 0.08 L/min/m2 in the treprostinil group and − 0.07 ± 0.07 L/min/m2 in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 ± 2 U × m2 in the treprostinil group and increased by 1 ± 1 U × m2 in the placebo group (p = 0.006). The placebo-corrected median improvement from baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055); this improvement appeared to be dose related. Dyspnea fatigue scores also improved in the treprostinil group compared with the placebo group (p = 0.014). Adverse events included infusion site pain and typical side effects related to prostaglandins, and were tolerated by most patients.

Conclusions:

Continuous subcutaneous infusion of treprostinil in patients with PAH associated with CTD improved exercise capacity, symptoms of PAH, and hemodynamics.

Section snippets

Materials and Methods

In a large, multicenter, double-blind, placebo-controlled, 12-week trial, 470 patients with PAH aged 12 to 75 years were randomized to receive a continuous, subcutaneous infusion of treprostinil or placebo, according to the following inclusion criteria (previously described13): NYHA functional class II, III or IV despite treatment with conventional therapy (ie, anticoagulants, oral vasodilators, diuretic agents, cardiac glycosides, and supplemental oxygen), mean pulmonary artery pressure (PAPm)

Results

Ninety patients from the original 470 patients enrolled in the PAH multicenter trial were diagnosed with PAH associated with CTD. Baseline demographics and hemodynamics for patients with CTD are shown in Tables 1, 2, respectively. The baseline 6MW distance was 280 ± 13 m for the treprostinil group, and 296 ± 13 m for the placebo group (p = 0.28). There were no significant differences in baseline demographics, hemodynamics, 6MW distances, CTD diagnosis, or NYHA functional class between the

Discussion

In the subset of patients with PAH associated with CTD from the large PAH multicenter trial studying treprostinil vs placebo, continuous subcutaneous infusion of treprostinil improved exercise capacity, hemodynamics, dyspnea fatigue rating, and physical aspects of quality of life compared with placebo. Adverse events with treprostinil were similar to those observed in clinical trials of epoprostenol,9 with the exception of infusion site pain, which was seen in the majority of

Appendix

The Treprostinil Study Group: Alejandro Arroliga, MD, The Cleveland Clinic; David Badesch, MD, University of Colorado Health Sciences Center; Issahar Ben-Dov, MD, The Chaim Sheba Medical Center, Israel; Robert Bourge, MD, University of Alabama Medical Center; Carol Black, MD, Royal Free Hospital, United Kingdom; Paul Corris, MD, Freeman Hospital, United Kingdom; Ben deBoisblanc, MD, Louisiana State University Medical Center; Teresa DeMarco, MD, University of California San Francisco; Ramona

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This work was funded by United Therapeutics Corporation, Research Triangle Park, NC.

The authors have financial relationships with United Therapeutics Corporation, the sponsor of the study. These relationships include consulting and support for work as investigators and study coordinators.

A list of study participants is given in the Appendix.

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