Current epoprostenol use in patients with severe idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension: Data from the French pulmonary hypertension registry

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Abstract

Objectives

The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated.

Methods

This observational study evaluated newly diagnosed (≤ 1 year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment.

Results

After 4 months of epoprostenol therapy, improvement was observed for treatment naïve patients (n = 43) and for patients who had received previous PAH-specific therapy (n = 35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p < 0.0001) and 41 m (p = 0.03), cardiac index increased by 1.2 (p < 0.0001) and 0.5 L·min 1·m 2 (p = 0.006), and pulmonary vascular resistance decreased by 700 (p < 0.0001) and 299 dyn·s·cm 5 (p = 0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p = 0.03).

The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3 years, respectively).

Conclusions

First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH.

Introduction

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure and pulmonary vascular resistance, leading to right heart failure and death. Without specific treatment, idiopathic, heritable and anorexigen-associated PAH (IHA-PAH) is associated with a 2.8-year median survival time after diagnosis [1].

Over the last two decades, new therapeutic agents have considerably improved the clinical status and prognosis of PAH patients. Three classes of drugs, each affecting different mechanisms involved in the pathogenesis of PAH, are currently available for the management of PAH [2]. Endothelin receptor antagonists (ERAs) and phosphodiesterase type-5 (PDE-5) inhibitors are administered orally, whereas prostacyclin therapies are delivered by continuous intravenous (i.v.) or subcutaneous infusion, or nebulization. However, PAH continues to cause substantial morbidity and mortality [3].

Epoprostenol, a synthetic analog of prostacyclin, was the first therapy approved by the FDA for the treatment of PAH (1995). Two prospective studies initially showed sustained clinical benefit on hemodynamics and exercise capacity with i.v. epoprostenol compared with conventional therapy for idiopathic PAH (IPAH) patients [4], [5]. In the 12-week study by Barst et al., epoprostenol significantly improved short-term survival compared with conventional therapy [5]. The positive impact of epoprostenol on long-term survival in IPAH has subsequently been described in several single center, observational, uncontrolled trials [6], [7], [8], [9].

Recent evidence-based guidelines recommend i.v. epoprostenol for the long-term treatment of PAH in patients with New York Heart Association (NYHA) functional classes III and IV and in patients who failed to respond to oral or inhaled treatment [10], [11]. Combinations with other PAH medications is possible [2], but limited data have been published on epoprostenol therapy since the advent of oral treatments.

In this study, we describe the use of epoprostenol in the management of patients with IHA-PAH. The effect of epoprostenol treatment administered as first-line or add-on therapy on clinical and hemodynamic status, as well as on survival was investigated in a cohort of consecutive patients enrolled in the French pulmonary hypertension (PH) registry.

Section snippets

Study design

This observational study evaluated all incident i.e. newly diagnosed (≤ 1 year), consecutive patients with IHA-PAH who were enrolled in the French PH registry between 2006 and 2010 and treated with i.v. epoprostenol. The French PH registry was initiated in 26 French reference centers and enrolled consecutive patients with PH. IHA-PAH patients were characterized as nontreatment-naïve for those who had received PAH-specific therapy after enrolment and before epoprostenol initiation and

Study population

The study evaluated 209 adult patients enrolled in the French PH registry who were newly diagnosed (≤ 1 year) with PH and treated with i.v. epoprostenol. Most patients on epoprostenol were in PH group 1, and had IHA-PAH or PAH associated with connective tissue disease (Fig. 1). The current analysis focused on the 78 IHA-PAH patients. IHA-PAH patients were further characterized as nontreatment-naïve (n = 35) for those who had received PAH-specific therapy after enrolment and before epoprostenol

Discussion

The present study describes the use of epoprostenol in the current management of patients with severe IHA-PAH enrolled in the French PH registry. With the availability of novel disease-specific therapies, treatment options for PAH patients have significantly broadened since the era when epoprostenol was the only approved PAH treatment. In the historical cohorts described by Sitbon et al. [9] and Mclaughlin et al. [8], patients exclusively received epoprostenol. In the present study, in line

Funding

This is an academic registry and was supported in part by Actelion Pharmaceuticals Ltd., which funded statistical analysis and editorial assistance.

Conflicts of interest

Emmanuel Bergot has received payment for board membership from Actelion and Eli Lilly, for lectures from Actelion, Eli Lilly, and Pfizer, and for travel/meeting expenses from Actelion, Eli Lilly, GlaxoSmithKline, and Pfizer.

Olivier Sitbon has received payment for consultancy and lectures from Actelion, Bayer HealthCare, Eli Lilly, GlaxoSmithKline, Pfizer, and United Therapeutics, and for the development of educational presentations from Actelion, Eli Lilly, and Pfizer. His institution has

Acknowledgments

The authors thank Jean-Christophe Lemarié for the statistical analyses (Effi-Stat, Paris, France) and Sylvie I. Ertel (Sundgau Medical Writers, Habsheim, France) for the editorial assistance.

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