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

Iloprost
This is a synthetic stable analog of epoprostenol that can be delivered via IV or inhaled routes. The IV preparation is not approved in the US. The inhaled form was approved by the FDA in 2004. Iloprost has a relatively short halflife (20–30 minutes) and requires six to nine inhalations daily through a handheld nebulizer device, with each treatment taking at least five to 10 minutes. Typically, patients do not interrupt sleep for their inhaled treatments.

Clinical Trials
IV use of iloprost has been evaluated in only two small studies, suggesting similar acute and intermediate-term (seven weeks) improvement in hemodynamic response and exercise tolerance compared with epoprostenol.^13,14 The first of these was by Olschewski et al.,¹⁵ who compared inhalations of iloprost six to nine times daily with inhalation of placebo in 203 patients with selected forms of severe PAH or chronic thromboembolic PH with functional class III or IV symptoms in spite of conventional therapy. This three-month randomized, double-blind, placebo-controlled, multicenter trial utilized a composite primary end-point of a 10% improvement in 6MWT distance and functional class improvement in the absence of clinical deterioration or death. This composite end-point was achieved in 17% of treated patients compared with 5% of patients receiving placebo (p=0.007). The treatment effect on 6MWT distance was a mean increase of 36m in the overall population in favor of iloprost (p=0.004) and 59m in the subgroup of patients with IPAH. This study also found statistically significant improvement in hemodynamics (p<0.001), NYHA functional class (p=0.03), dyspnea (p=0.015), and quality of life (p=0.026).¹⁵

In the second, more recent, study, Opitz et al.¹⁶ evaluated the long-term clinical efficacy of inhaled iloprost as first-line monotherapy in patients with IPAH. Clinical, hemodynamic, and exercise parameters were obtained at baseline, after three and 12 months of therapy, and yearly thereafter for five years prospectively in 76 IPAH patients with four end-points: death, transplantation, change to IV therapy, and addition of other active oral therapy. During this follow-up period, 11 patients (14%) died, six patients (9%) underwent transplantation, 25 patients (33%) were switched to IV prostanoids, 16 patients (23%) received additional oral PAH therapies, and 12 patients (17%) discontinued inhaled iloprost for other reasons. Eventfree survival rates at one and two years were 53 and 29%, respectively.16 While these long-term results may not appear optimal, it must be considered that this was a non-randomized study. At present, inhaled iloprost is most commonly utilized when oral therapy provides suboptimal results in a patient not deemed ill enough for IV therapy, or in some patients who appear well enough to be weaned off IV therapy. However, weaning IV therapy is a scenario in which there is not a clear standard of care.

Beraprost
Beraprost is a prostanoid that is stable at body temperature and gastric pH and was thought to be promising due to oral dosing. Okano et al.¹⁷ reported an improvement in mean PVR from 19.3 to 14.3 Wood units, and an improvement in mPAP from 66 to 58mmHg in 10 of the 12 WHO class III or IV IPAH patients after two months of oral beraprost. A long-term benefit of at least one functional class was observed in eight patients with a mean follow-up of five months. The remaining four patients died of progressive disease.¹⁷ Galie et al.¹⁸ reported the results of a randomized, double-blind, placebo-controlled, multicenter study designed to determine the effects of 12 weeks of oral administration of beraprost sodium on exercise capacity, symptoms, and cardiopulmonary hemodynamics in 130 NYHA class II and III patients with PAH. The mean difference in 6MWT distance between the two groups was 25m (p=0.036) at 12 weeks. There were no statistically significant differences in either cardiopulmonary hemodynamics or functional class.¹⁸ Another double-blind, randomized, placebo-controlled study in 116 PAH patients with oral beraprost failed to show long-term improvement.¹⁹ This medication has not been approved by the FDA.

Combination Therapy With Prostacyclins
Combination therapy is an appealing and promising concept that is being studied in randomized clinical trials.²⁰ It has a sound scientific basis, with multiple available agents working through different mechanisms. Nonetheless, properly designed studies are required to prove the benefit of this approach.

Intravenous Epoprostenol and Oral Bosentan Combination Therapy (The BREATHE-2 Trial)
In a double-blind, placebo-controlled prospective study, 33 patients with PAH on epoprostenol therapy were randomized for 16 weeks in a 2:1 ratio to bosentan 62.5mg twice daily for four weeks then 125mg twice daily, or placebo.²¹ At the end of 16 weeks, there was a trend suggesting greater improvement (although statistically non-significant) with the combination treatment in all measured hemodynamic parameters. Total pulmonary resistance declined by 41% from baseline to week 16 of treatment (from 1,697±142 to 1,016±78dyn/s/cm2) in the bosentan–epoprostenol group compared with 23% in the placebo–epoprostenol group (p=0.08). Cardiac index rose by 49% in the bosentan–epoprostenol group compared with 38% in the placebo–epoprostenol group. mPAP fell by 9% (versus 2%) and PVR declined by 35% (versus 26%) in the bosentan–epoprostenol group. Functional class improved in 59% of patients receiving combination therapy compared with 45% of patients receiving epoprostenol monotherapy.²¹ In the combination group there were two deaths during the study and one death shortly after study drug withdrawal due to clinical worsening. There were no deaths in the placebo group.

Inhaled Iloprost and Oral Bosentan Combination Therapy (The STEP Trial)
McLaughlin et al.²² studied inhaled iloprost in patients who remained symptomatic (functional class III or IV) after receiving a stable dose of bosentan for at least three months. In this multicenter, placebo-controlled, randomized safety trial, 67 patients with PAH (94% NYHA functional class III, mean baseline 6MWT 355m) were randomized to receive inhaled iloprost six to nine times per day or placebo. After 12 weeks, the primary efficacy measure—post-inhalation 6MWT distance—improved by 30m in the iloprost group and by 4m in the placebo group, for a placebo-adjusted difference of 26m (p=0.051). There were also improvements in NYHA functional class (p=0.002), time to clinical worsening (p=0.02), post-inhalation mPAP (p=0.001), and PVR p=0.001). Although limited by a small sample size, this combination therapy appeared to be safe and well tolerated.²²