Hospitalization and survival in patients using epoprostenol for injection in the PROSPECT observational study.

BACKGROUND: Few studies have prospectively reported outcomes in patients with pulmonary arterial hypertension (PAH) treated with epoprostenol in the modern-day era of oral therapy and combination treatments. The Registry to Prospectively Describe Use of Epoprostenol for Injection (Veletri, prolonged room temperature stable-epoprostenol [RTS-Epo]) in Patients with Pulmonary Arterial Hypertension (PROSPECT) was established to prospectively describe the course of PAH in patients prescribed RTS-Epo. METHODS: PROSPECT is a multicenter, US-based drug registry of primarily group 1 patients with PAH treated with RTS-Epo who were parenteral-naive or parenteral-transitioned at enrollment. Patients were followed until discontinuation of RTS-Epo, withdrawal, loss to follow-up, death, or end of study (maximum 1 year). One-year freedom from hospitalization (FH) and survival estimates were summarized by prostacyclin history (parenteral-naive or parenteral-transitioned), sex, and chronic renal insufficiency (CRI). RESULTS: A total of 336 patients were included. The overall 1-year FH estimate was 51.0% ± 2.8% and was lower in parenteral-naive patients than parenteral-transitioned patients (42.8% ± 4.3% vs 57.1% ± 3.7%, respectively; P = .002). FH estimates were lower in male patients than female patients (38.3% ± 5.9% vs 54.6% ± 3.2%, respectively; P < .015) and in patients with CRI than patients without CRI (17.0% ± 8.4% vs 53.7% ± 2.9%, respectively; P < .001). The overall 1-year survival estimate was 84.0% ± 2.1%. Survival was poorer in parenteral-naive patients, male patients, and patients with CRI. CONCLUSIONS: Risk of hospitalization and mortality remain high in patients with PAH. In particular, patients who are parenteral-naive at initiation of RTS-Epo therapy, male patients, and patients with CRI require close monitoring and aggressive clinical management.

Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease.

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/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2) 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.

The prostacyclin analogue treprostinil blocks NFkappaB nuclear translocation in human alveolar macrophages.

Primary pulmonary hypertension (PPH) is characterized by increased pulmonary arterial pressure and vascular resistance. We and others have observed that inflammatory cytokines and infiltrates are present in the lung tissue, but the significance is uncertain. Treprostinil (TRE), a prostacyclin analogue with extended half-life and chemical stability, has shown promise in the treatment of PPH. We hypothesize that TRE might exert beneficial effects in PPH by antagonizing inflammatory cytokine production in the lung. Here we show that TRE dose-dependently inhibits inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and granulocyte macrophage colony-stimulating factor) secretion and gene expression by human alveolar macrophages. TRE blocks NFkappaB activation, but IkappaB-alpha phosphorylation and degradation are unaffected. Moreover, TRE does not affect the formation of the NFkappaB.DNA complex but blocks nuclear translocation of p65. These results are the first to illustrate the anti-cytokine actions of TRE in down-regulating NFkappaB, not through its inhibitory component or by direct binding but by blocking nuclear translocation. These data indicate that inflammatory mechanisms may be important in the pathogenesis of PPH and cytokine antagonism by blocking NFkappaB may contribute to the efficacy of TRE therapy in PPH.